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SCRATCHING YOUR HEAD PSYCHIATRY II:
How to Think INSIDE the Allopathic Box…
 [and Practice Precisely, Effectively, and to
             Maximum Benefit]



   Louis B. Cady, MD – CEO & Founder – Cady Wellness
  Institute Adjunct Assoc. Professor – Indiana University School
              of Medicine Department of Psychiatry
   Child, Adolescent, Adult & Forensic Psychiatry – Evansville,
                             Indiana
                  (c) 2012 Louis B. Cady, M.D. - all rights reserved
“Slumber not in the
tents of your fathers.
The world is advancing.
Advance with it.”

 - Giuseppe Mazzine
Relevance for your practice
• ALL PRESCRIBERS - don’t kill your patient
  with a drug-drug interaction.
• ALL PARTICIPANTS - Know bad/stupid
  psychopharmacology when you see it.
  – Be able to DO SOMETHING about it.
• Don’t diagnose someone as having “drug
  problems” when they DON’T.
• Better “MOA” understanding
A quick look back in history




The Interpretation of   Ugo Cerletti 1935
                                            Prozac - 1987
Dreams – 1885 - 1890
The Therapeutic Trifecta of Psychiatry:
             Shrinking
             Shocking
            or Drugging
     [Supposedly the only three things
        you could do to a patient’s
                 brain…]
Dangers with
            Psychiatry/psychotropics
• Failure to diagnose
    – (E.g “head case” and then they die of a medical problem)
• Failure to adequately treat
• Failure to prescribe accurately (Rx-rx interaction)
• Giving people side effects
• Using the wrong drug
• Ignorance about best options because “I always did it that
  way.”
• Getting people addicted
• Practicing beyond your ability and expertise
• Violating black box warnings
*ACCURATE MEDICAL diagnosis a malpractice suit
 Depression & Anxiety & “mood disorder due to a
                  in 1 Easy Lesson
    general medical condition” AND r/o bipolar disorder

DEPRESSION                    Gen. ANXIETY D.O.
  SIG: E- CAPS!               •Somatic Sx (“energy”,etc.)
• Sleep                       •WORRY
• Sadness                     •Irritability
• Interest loss               •Concentration
• Guilt                       •Keyed up
• *Energy                     •Insomnia (“sleep”)
• Concentration               •Restlessness
• Appetite             BEWARE BEWARE – “too much”
• Psychomotor Sx       energy
• Suicidal thinking           SWICKIR is Quicker:
                              Worry + 3 = GAD (Baughman)
5of 9 with 1 of 2 x 2 weeks
Lifetime Prevalence of
Common Psychiatric Disorders

 Major depressive disorder                                                             17.1%
     Alcohol dependence                                                        14.1%

   Social anxiety disorder                                                   13.3%

                    PTSD                                     7.8%
  Generalized anxiety d.o                          5.1%
                     PMDD                          5%*

             Panic disorder                 3.5%
                          OCD            2.5%


                                0    2      4        6      8       10 12 14 16 18
                                                   Lifetime prevalence (%)


*In menstruating women.
                                Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000.
Epidemiology of Depression
Prevalence of Major Depression
               20
                          point prevalence (30 day)
               15         lifetime prevalence

  Percent      10
 of Patients

               5


               0
                        Epidemiologic           National Comorbidity
                    Catchment Area (ECA)            Survey (NCS)
                             Regier et al., 1988; Blazer et al., 1994
PHQ-9 Symptom Checklist
                                                                                            More      Nearly
    1. Over the last 2 weeks, how often have you                      Not       Several   than half   every
       been bothered by the following problems?                      at all      days     the days     day
                                                                       0           1          2         3

   a.    Little interest or pleasure in doing things                                                
   b.    Feeling down, depressed, or hopeless                                                       
    c.   Trouble falling or staying asleep, or sleeping too much                                    
   d.    Feeling tired or having little energy                                                      
   e.    Poor appetite or overeating                                                                
    f.   Feeling bad about yourself, or that you are a failure…                                     
   g.    Trouble concentrating on things, such as reading…                                          
   h.    Moving or speaking so slowly…                                                              
    i.   Thoughts that you would be better off dead…                                                
                                                                   Subtotals:     3          4          9
                                                                    TOTAL:        16

Kroenke 2001.
Depression—Impact on the
            Healthcare System
• Compared with those without
  depression, depressed individuals:
   – Utilize all types of healthcare services more
     often
   – Incur 1½ to 2 times greater healthcare costs
   – increased length of hospital stay
   – significant worsening of physical, social, and
     role functioning

Simon 1995; Luber 2000; Verbosky 1993; Wells 1989.
Comorbidity of Depression and
                Anxiety
  Disability                                                     % Patients
                                                                 Disabled 3+ Days


   GAD + MDD                                                     33.7%

  MDD/no GAD                                                     19.45%

  GAD/no MDD                                                      16.9%
no GAD/no MDD                                                      3.1%

                0   5   10   15   20   25   30   35    40   45
        Percent of Patients With ≥1 Disability Day in Past Month
                                                      Wittchen, Depress Anxiety, 2002
Where does ADHD come from?
Kids and Adults – Differences in
         HYPERACTIVE domain
AS A CHILD:                       AS AN ADULT:
• Squirming, fidgeting            • Work inefficiencies
• Cannot stay seated              • Can’t sit through meetings
• Cannot wait turn                • Cannot wait in line
• Runs/climbs excessively         • Drives too fast
• Cannot play quietly             • Self-selects very active job
• On the go/driven by motor       • Cannot tolerate frustration
• Talks excessively               • Talks excessively
• Blurts out answers              • Makes inappropriate
• Intrudes, interrupts others        comments
                                  • Interrupts others
 Sources: DSM-IV (TR). APA 2000:85-93)
 Weiss MD, Weiss JR. J Clin Psychiatry 2004;65(Suppl 3):27-37.
Horrigan J, et al. Presented at 47th Annual AACAP Meeting:
October 24-29, 2000. New York, NY.
Persistence of ADHD Into Adulthood
• ADHD is a heterogeneous disorder associated with
  considerable disability and comorbidity that, in many cases,
  persists into adulthood1
    – Some studies have found persistence as high as 36.3% 2

• Mood, anxiety, and substance use disorders are
  the most common comorbid disorders in adults with ADHD 3
• Current prevalence of ADHD persistent into
  adulthood 4.4%4 (5% by new study – Willcut – Neurotherapeutics 2012
• Much of the treatment of adult ADHD can be based on
  experience in treating children/adolescents5
 1. Barkley et al. J Abnorm Psychol. 2002;111:279-289.
 2. Kessler RC et al. Biol Psychiatry 2005 June;57(11):1442-51. [retrospective review of 3,197 14-44 yo
    respondents in NCS-R]
 3. Biederman et al. Am J Psychiatry. 1993;150:1792-1798. 4. Kessler et al. Am J Psychiatry. 2006;163(4):716-
    23. 5. Dodson WW. J Clin Psychol. 2005;61:589-606.
Diagnostic Pearls - Cady
• How’s work?
    – How has your employment history been?
• How’s your mood? Your marriage (relationship)?
• How was school for you?
• Are people nervous driving with you?
• Are there periods of time when you have too much
  energy for no particular reason?
• Do you ever have to have a beer at the end of the day to
  relax?
    – [gently lead in to other substances, especially stimulants that
      may have a CALMING effect]
    – “Have you ever taken any of your child’s ADD Rx?” [or other
      stimulants, energy drinks, diet pills, or cocaine]
Pharmacology Failures…

1. “Begin with the end in mind.” (Covey)
2. Start LOW – (rule of thumb – ½ what the
   drug rep and package insert says!)
3. Go up to the maximum tolerated dosage,
   with finesse.
  – Tell them about “Goldilocks”
1. If it doesn’t work, add something
   complimentary (that makes sense).
THE FACTS
• SSRI’s treat depression AND/OR anxiety
• Patients may INITIALLY need something else for daytime
  anxiety or sleep.
• BZD’s of choice:
   – clonazepam 1 mg tablets – ½ to 1 twice daily to three
     times daily
   – Diazepam – 5 mg =- ½ - 1 ½ twice daily to three times
     daily
       • (first pass and second pass effects)
• ANTIANXIETY RX (non BZD) – Buspirone, per package
  insert. Push to 20 mg THREE TIMES DAILY or to the
  point of maximum tolerability for 4 – 6 weeks AT THAT
  DOSE.
   – Start with 5 mg.     Can use WITH SSRI’s
AVOID Alprazolam (Xanax ®)

• Addicting (and rapidly so)
• Can have seizures if rapidly withdrawn
  (structurally similar to carbamazepine)
• MD’s shot over it.
• NOT an “anti-anxiety” medication
• NOT a sleeper.
• Even if they need a BZD for anxiety, it
  doesn’t have to be Xanax.
Sleepers – my preferences
• Rozerem (brand) (a melatonin analog) – 8 (up to 16* mg) at
  bedtime. VASTLY under-rated. May need to take 2 weeks
  before adequate effect. (* off-label dose)
    – Dual acting agent – homeostatic and circadian effects. 70x
      as potent as melatonin.
    – Melatonin SR may also be a good agent.
• Trazodone (50 – 150mg ½ - 2 hrs before HS. (Note, off
  label “unapproved.” Warn on priapism).
• Lunesta (brand) – 2 – 3 mg. Try samples. Have
  mouthwash on hand. (Probably most predictable agent)
• Ambien 12.5 mg CR (brand) – legitimately lasts longer than
  zolpidem. Probably not as effective as Lunesta.
• Zolpidem – generic. People get hooked on it.
•   Paradigm: SYMPTOMATIC treatment – after depression is stabilized,
    fade out the sleeper
Why treatment failures occur: too much or too little…
     The REAL mechanism of action of SSRI’s




Animation © NEI, Inc. (Neuroscience Institute) and is used specifically with permission from
Stephen Stahl, MD, Ph.D.
Drug, drug...
who's got the
       drug?
Depression/anxiety Rx:
       •   TCA
       •   Venlafaxine (Effexor)
       •   Duloxetine (Cymbalta)
       •   Mirtazapine (alpha 2)
       •   Desmethylvenlafaxine
           (Pristiq)




                   & others….
Side Effects & Drug Interactions:
The Doc Cady “Can’t s” of the TCA’s
         Pee
                   ANTICHOLINERGIC/
        Poop       ANTIMUSCARINIC
        Spit       EFFECTS

       Spurt
       Focus
       Think
      Stand up    Alpha-adrenergic
    Stay awake      blockade
      Stay thin   "Antihistamine"
                     effects
“Drug-drug interactions”
   clinically relevant?!
Drug-drug interactions: chum for legal “sharks”
“Strattera [coupled with
Prozac or Paxil] has been
great for our admissions. ”
              -Dr. William Beute, MD
              Pine Rest Campus Clinic
              Grand Rapids, MI
              April 21, 2004
              [quoted with permission]
Cytochrome p-450 2D6 inhibition measured as %
  increase in “Desipramine AUC” – in vivo data

                                            Critically important when
                                            combining with other Rx
                                            metabolized through 2D6
                                                     pathways




Preskhorn, Alderman, et al. Pharmacokinetics of desipramine coadministered
with sertraline or fluoxetine. J. Clin Psychopharmacol 1994;14:90-98;
Escitalopram package insert - note – different source of data, but same method
Some drugs metabolized through
        cytochrome P-450 IID6 system
ADHD             Antibiotics         ANTI-PAIN
Amphetamines    •TMP & SMX
STRATTERA                           CODEINE!
                 •Ampicillin
Analgesics       •Erythromycin       Bronchodilators
•Acetaminophen   •Penicillin         •Theophylline
•Aspirin         •Tetracycline       Cardiac
Antacids         Antidepressants     •Digoxin; digitalis
Antiarrthymics   •TCA’s & “2P’s”     Cough
•Procainamide,   Antihistamines      •Dextromethorphan
•Quinidine
                 Antihypertensives   Diuretics
•Encainide
•Flecainide
                 Antipsychotics      •Chlorthalidone
Anticonvulsant   •Clozaril           •Furosemide
•carbamazepine   •Risperdal          •HCTZ
                 •Zyprexa            •Triamterine
The “not so selective” SSRI’s; how to
       “Do yourself a favor.”
drug                  SSRI?   2nd order effects   Side effects possible

Escitalopram          Yes     NOTHING             (excess serotonin side
(Lexapro) now                                     effects only)
generic
Sertraline (Zoloft)   Yes     Dopamine (1/3 as    Agitation, nervousness;
                              potent as           improved [ ]
                              amphetamine)
Citalopram            Yes     AntiH1              Sedation (note- FDA
(Celexa)                                          lowered max dose to
                                                  40mg)
Paroxetine (Paxil)    Yes     Ach                 Doped up, TCA effects,
                              NOT “NRI”           neurocognitive problems,
                                                  withdrawal. Sexual,
                                                  Prostate sxs
Fluoxetine            Yes     5HT2C               Agitation, appetite
(Prozac)                                          suppression
New Agents, New Mechanisms
(agent)                   (MOA)           Differentiating points

Venlafaxine (“IR” and XR) SSRI, NRI       Nausea, GI side effects, sxl
(Effexor)                                 dysfunction

Duloxetine (Cymbalta)     SSRI, NRI       Same. Better tolerated. For pain
                                          w/ dep.
Desvenlafaxine (Pristiq) – SSRI, NRI      Better tolerated
“son of Effexor”

Trazodone XR with         5HT2a/c         Legitimate effect on
Contramid® (OLEPTRO)      BLOCKER, mild   depression/anxiety without
                          SSRI            doping up.
Vilazodone (Viibryd)      SPA, SSRI       ONLY SPARI. Weaker “SSRI.”
                                          Targets 5HT1A. Less sexual side
                                          effects.
Bupropion (“XL” – not     “NDRI”          Possibility of anxiety & “wound
“SR”) (Wellbutrin)                        up.” Improved concentration.
                                          Push to 450 mg. SZ warning..
An illustrative study on picking your
          antidepressant…

   Duloxetine (Cymbalta) Versus
Escitalopram (Lexapro) and Placebo:
An 8-month, Double-Blind Trial in
 Patients With Major Depressive
            Disorder
 Pigott et al., Curr Med Res Opin, 2007
Retardatio
Comparison of Escitalopram and Duloxetine:
 HAMD (MMRM)
                 8-Month Trial
           17




                               Maier
                Subscales


                               Sleep



                                             *
                            Somatization
                            Anxiety/
                               Total Score




 *p<0.05
                                                 Pigott et al., Curr Med Res Opin, 2007
Comparison of Escitalopram and Duloxetine: 8-
                 Month Trial
Significantly Different Adverse Events (p<0.05 Duloxetine vs Escitalopram)




                               Percent of Patients

                                               Pigott et al., Curr Med Res Opin, 2007
Comparison of Escitalopram and
     Duloxetine: 8-Month Trial
Conclusions: they both worked the same;
side effects were worse with duloxetine
• Remission rates for both escitalopram and duloxetine
  continued to improve over time

• Significantly more escitalopram-treated patients
  continued treatment compared to duloxetine-treated
  patients

• Escitalopram showed significant improvement vs
  duloxetine on the HAMD17 sleep subscale

• Compared to escitalopram, duloxetine significantly
  increased pulse and systolic blood pressure

                                    Pigott et al., Curr Med Res Opin, 2007
Two New Agents You Need to Know
• Extended release Trazodone
  – NOT “son of Trazodone”
  – Possibility of legitimate antidepressant effect with anti-
    anxiety effect WITHOUT doping patient up.
  – A “SARI” – serotonin antagonist reuptake inhibitor
• Vilazodone – the only SPARI available.
• How to appreciate:
  – 5HT1A is receptor for antidepressant effect of serotonin
  – 5HT2A and 5HT2 C: anxiety, sleep disruption, sexual
    side effects.
  – ANYTHING which works preferentially on 5HT1A is
    GOOD!
XR Trazodone steady state dosing study

• (Levels done after 7
  days steady state)
• 300 mg XR Traz
  AUC comparable to
  100 mg IR Traz tid
• Cmax 42% lower
  than IR Trazodone
     – Translation – it
       doesn’t dope the
       patient up.



Kramer, WG et al. Once-daily Trazodone: Overview of Pharmacokinetic Properties.
Poster – ACCP 38th Annual Meeting, San Antonio, TX 2005
XR Trazodone Food Effect Study
                                            • PI says “take at night”

                                            • CMax increase by 86%
                                              (!!!) under fed conditions.
                                              Peak is at 7 hours post
                                              dose (with feeding).

                                            • Note – this may lead the
                                              enlightened prescriber to
                                              vary the time of dosing.


Kramer, WG et al. Once-daily Trazodone: Overview of Pharmacokinetic Properties.
Poster – ACCP 38th Annual Meeting, San Antonio, TX 2005
Vilazodone – a SPARI (per Stephen Stahl, MD, Ph.D.) –
      Serotonin Partial Agonist Reuptake Inhibitor




• Highly serotonergic. START LOW (5 mg).
• Because of 5HT1A agonism, LESS “SSRI” effect is
  required.
ADHD Rx for frontline medicine
• Desiderata – get control, and keep it consistent for
  predictable period of time
• Rules of thumb: don’t be guided on SIZE. START LOW.
  “Know the Biederman max” for MPH and amphetamine.
• Recommendations (for children and adult):
   – Focalin XR (Dexmethylphenidate XR) 5,10,15,20,30 and 40 mg
     capsules)
      • Rationale: MPH based. FAST. 8 – 10 hours. Can dose twice daily (off-
        label), a.m. >pm. (can also start with ½ capsule)
   – Vyvanse – (lisdexamfetamine [sic]) – 20,30,40,50,60,70 mg [= 7.5
     – 30 mg] amphetamine equivalents. Lasts 12 – 14 hours. (Can
     dissolve in water – per PI!).
   – Kapvay/Intuniv – FDA approved in kids.
      • Kapvay easier to use, better tolerated.
      • Intuniv more potent, but more side effects (sedation)
Practicing beyond your ability (and knowledge) –
      the second generation antipsychotics
• Definitions:
   – Mood stabilizer – something that stabilizes mood
     (Lithium, carbamazepine, VPA)
   – Antipsychotic – something you give someone who is
     PSYCHOTIC to get them UNPSYCHOTIC.
   – Antidepressant – something for depression.
   – “2nd generation antipsychotic (“SGA’s”) = S2/D2
     blockers.”
      • Can “stabilize mood” as well as function as antipsychotics
      • Now some FDA approved for either add-on use or single agents
        for “bipolar depression” (e.g., quietapine XR)
Know who you’re playing with
• SGA’s and WEIGHT GAIN (Cady experience)
   – olanzapine/risperidone > quietapine>
     aripiprazole/arsenapine> lurasidone/ziprasidone
      • (Zyprexa/Risperdal>Seroquel> Abilify/Saphris> Latuda/Geodon)
• EXPENSIVE: $400 – $600 /per month
• All will work for mania. NONE are pure “mood stabilizers.”
  Some make you fat.
• Some will work for depression but dope you up.
• Much less risky than 1st generation for tardive dyskinesia.
• Axiom: refine your psychopharmacology before going to
  look for an SGA.
• If you have to use one (for bipolar or psychosis, Lurasidone
  is probably most benign – 40 – 80 mg twice daily (or 160
  mg HS)
Cady recommendation for SGA’s in
               primary care
• As little as possible.
• Do NOT use as primary mood stabilizers for bipolar disorder.
  Use lithium (Type I) VPA (Type I/II) or Lamotrigine – which is
  a real option. Check levels and labs as needed
• Can use if single, or better yet, DOUBLE mood stabilizers
  don’t work.
• Abilify (only “dopaminergic” SGA) probably best for
  antidepressant augmentation at LOW DOSE.
   – 2 – 4 or 5 mg is optimum dose for this. (Start with ½ of a 2
      mg and go up)
   – Onset is FAST when it happens.
• Olanzapine is most dependable for rapid onset and control of
  manic episode, or agitation, or EXTREME PANIC & anxiety
  (off label).. Lurasidone may be best tolerated.
A quick look back in psychiatric tx:




The Interpretation of   Ugo Cerletti 1935
                                            Prozac - 1987
Dreams – 1885 - 1890
The Therapeutic Trifecta of Psychiatry:
             Shrinking
             Shocking
            or Drugging
        [Supposedly] the only three
     things you could do to a patient’s
                 brain…]
STAR*D Study demonstrates that current
             treatment has limited effectiveness




                                                                          47
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
                                                                                    Systemic Drug Side Effects
                                                                                   Weight Gain
                                                                                                      Fatigue

                                                                                   Constipation      Headache/
                                                                                                       Migraine
                                                                                   Diarrhea
                                                                                                      Abnormal
                                                                                   Nausea             Ejaculation
                                                                                   Drowsiness        Impotence
                                                                                   Insomnia          Sweating
                                                                                   Decreased         Tremor
                                                                                    Libido
                                                                                                      Treatment
                                                                                   Nervous            Discontinuati
                                                                                    Anxiety            on Side
                                                                                                       Effects
                                                                                   Increased
                                                                                    Appetite          Weakness
                                                                                   Decreased         Dry Mouth
Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J       Appetite
Psychiatry; McGrath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file)
                                                                                                      Dizziness
ECT – origins
• Origin in 1700’s – Middlesex Hospital
   – machine with weak electrical current used for range of illnesses.
   – John Birch, English neurosurgeon, used it to shock the brains of
     depressed patients
   – Benjamin Franklin, after shocked, recommended electric shock for
     tx of mental illness
• Ugo Cerletti – 1935 – noted (incorrectly) that epilepsy and
  schizophrenia didn’t occur in same patient
• Problems with ECT – memory loss, anesthesia risk
• Cost of $6400 for eight treatments
• 80% improvement
• 33,000 hospitalized Americans – ECT in 1980, last year for
  NIMH figures
   – http://www.faqs.org/health/topics/19/Electroconvulsive-therapy.html
But even before Freud…
• Electromagneitc
  induction – 1831
  (Michael Faraday &
  Joseph Henry)
• 1st demonstrated by
  Faraday August 29,
  1831
Faraday’s Law of Induction

      TMS     Induced neuronal
     Magnetic      current
      field
From electricity to
    magnetism
• Bartholow, R (1874)
   – Stimulation of human brain
     (exposed cortex) of patient with
     cranial defect.

• d’Arsonval – “Phosphenes
  and vertigo” induced inside
  powerful magnetic coil

• Silvanus P. Thomson, Ph.D.
  – new type of magnetic     Thompson, SP. “A Physiological
                             Effect of an Alternating Magnetic
  stimulation (1910)         Field.” Proceedings of the Royal
                                        Society of London B82:396-399, 1910
First patent application for magnetic
               therapy:
• 1902 Adrian Pollacsek
  and Berthold Beer –
  Vienna, Austria for a
  “therapeutical apparatus”
• Electromagnetic coil,
  placed over the skull was
  noted to “pass vibrations
  into the skull” and “treat
  depression and
  neuroses.”
A quick look back in psychiatric history - redux

 Shrinking          Zapping          Shocking           Drugging




Freud: The          Silvanus P.    Ugo Cerletti 1935   Prozac - 1987
Interpretation of   Thompson,
Dreams – 1885 -     Ph.D. (1910)
1890
First modern TMS:
• Barker AT, et al. “Non-
  invasive magnetic
  stimulation of the human
  motor cortex. The
  Lancet 1:1106-1107,
  1985.
• 1st device – designed by
  Barker – Univ. of
  Sheffield, England.
   – 100 microsecond, 2 T
     pulse
Coil types and rationale




From Matt Edwardson, MD – Research Fellow and Acting
Instructor, Dept. of Neurology, Univ. of WA 10/16/2011
An unusual side effect
           of imaging (2004)…




• CONCLUSIONS: “These preliminary data suggest
  that the EP-MRSI scan induces electric field that
  are associated with reported mood improvement in
  subjects with bipolar disorder.”
Scratching Your Head Psychiatry II: How to Practice INSIDE the Allopathic Box
NeuroStar TMS Directly Depolarizes
        Cortical Neurons



                  Neuron
                            Pulsed magnetic fields
                            from NeuroStar:
                            •induce a local electric
                            current in the cortex
                            which depolarizes
         Neurons are        neurons
      “electrochemical      •eliciting action potentials
    cells” and respond to   •causing the release of
     either electrical or
    chemical stimulation    chemical
                            neurotransmitters
NeuroStar Releases Neurotransmitters
                 in the Brain
                                                           These effects
                          Depolarization of neurons in
                           the DLPFC causes local         are associated
                           neurotransmitter release
                                                                  with
                                                         improvements in
                                                    Dorsolateral
                                                       prefrontal
                                                            depressive
                                                           cortex
                                                             symptoms
                                                         Anterior
                                                  cingulate
                                                     cortex

                                                          Kito (2008) J Neuropsychiatry Clin
                                                          Neurosci
  Depolarization of pyramidal
  neurons in the DLPFC also                 Activation of deeper brain
causes neurotransmitter release          neurons then exerts secondary
    in deeper brain neurons              effects on remaining portions of
                                              targeted mood circuits
ECT                        TMS

Anesthesia, LOC        ECT vs. TMS No
                       Yes

Induction of seizure   Yes                        No
Systemic effects       Anesthetic drugs,          none
                       increase HR
Treatment schedule     3X/ week (8 -15 tx)        Daily, M-F, six weeks (30
                                                  tx)
Rapidity of onset      2 – 3 treatments           2 – 3 weeks

Mechanism of action    SEIZURE. Massive NT        Precise, LOCAL release
                       release; rise in sz        of NT’s. Reactivation of
                       threshold                  neural circuits.
Side effects           Memory loss, confusion     Essentially none (mild HA
                                                  1st week)
Psychosocial impact    can’t work                 Drive to and from tx’s,
                                                  work improved
After-effects          Mild (usually transient)   None. Pro-cognitive
                       memory loss
Insurance coverage     Almost always              Rare. Improving
From Michael Farraday to today
Scratching Your Head Psychiatry II: How to Practice INSIDE the Allopathic Box
Does it work?
• Original registration trial
  – 307 major depressed patients
     • 67% women
     • 93% recurrent depressives
     • 43% had been hospitalized already
  – 42 sites
  – Treatment per label
• Results: ½ patients responded; 1/3 of
  patients remitted.
• 80% patients completed the treatment.
Who Was Studied?
    • Primary diagnosis: DSM-IV Major Depressive
      Disorder
           – Unipolar type, non-psychotic
           – Moderate to severe symptoms at baseline
           – Approximately one-third of patients had a co-morbid anxiety
             disorder (OCD excluded)
    • Antidepressant Treatment History:
           – Average number of antidepressant medication trials in current
             episode = 4 (range: 1 to 23 attempts)
                   • Majority of treatment attempts were unable to achieve adequate
                     dose and duration of treatment due to intolerance
           – In the indicated patient population, all patients failed to
             achieve satisfactory benefit from one antidepressant
             medication at an adequate dose and duration in current
             episode
                                               65
Demitrack and Thase (2009) Psychopharm
     Bulletin
O’Reardon, JP, et al. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation in
the Acute Treatment of Major Depression: A Multi-Site Randomized Controlled Trial.
Biol Psychiatry 62:1208-1216.
Optimization of TMS (‘OPT-TMS’) Study



Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD;
Martina Pavlicova, Phd; Berry Anderson, Phd, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD;
Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD




                                  Major Findings:
• NIMH-funded, independent of industry       • MADRS total score decreased:16.6%
• N=190 patients, 4 premier academic sites     (Active) vs 6.9% (Sham) p=0.01
• Primary outcome measure:                     (Effect size: 0.51)
  % Remission - Active 15% vs Sham 4% (P = • 30% of patients achieved remission
  0.015); Odds Ratio of achieving remission:   in open-label extension phase
  4.2 (95%CI, 1.3-13.2)                      • Excellent safety and adherence

Conclusion: “Daily left prefrontal rTMS as monotherapy produced
statistically significant and clinically meaningful antidepressant therapeutic
effects greater than sham.”
Recent TMS Literature Review
• Roughly 30 controlled clinical research studies to date
• Most recent meta-analysis (Slotema, et al, 2010):
     – Included analysis of 34 studies involving 1,383 patients
     – Estimated standardized effect size = 0.55 (P < 0.001)
     Conclusion: “…rTMS  deserves a place in the
         standard toolbox of psychiatric treatment
         methods, as it is effective for depression…and
         has a mild side effect profile….”
 1.Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric
 treatment methods to include repetitive transcranial magnetic stimulation (rTMS)J Clin Psych 71(7):873-84.

 2.Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over
 the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol
 Medicine, 39:65-75.
NeuroStar TMS Therapy: Safety
                          Overview
    • No systemic side effects
    • No adverse effect on cognition
    • Most common adverse event associated with
      treatment was scalp pain or discomfort
            – < 5% of patients discontinued due to adverse events
    • No seizures with NeuroStar device during clinical
      studies (over 10,000 treatments)
    • Rare risk of seizure with NeuroStar TMS in post-market
      use (0.003% per treatment, <0.1% per acute treatment
      course) (>150,000 treatments in post-marketing experience to
          date)
    • Long term safety demonstrated in 6 months follow-up
Janicak, et al. J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010.
No Evidence of Emergent Suicidal Ideation


                                               4.0
                                                                NeuroStar TMS Therapy (n=155)
               HAMD Item 3 Suicidal Ideation




                                               3.5
                                                                Sham TMS (n=146)
                                               3.0
                     Shift Score (%)*




                                               2.5

                                               2.0

                                               1.5

                                               1.0

                                               0.5

                                               0.0
                                                     Baseline         Week 2         Week 4          Week 6
            * Shift Score indicates the percent of subjects who experienced a change in HAMD Item 3 score from 0 or 1 at baseline
              to 3 or 4 at later point in time.


Janicak (2008) J Clinical Psychiatry.
Long Term Follow Up After Acute
                                                 Treatment

     RCT or Open-Label Extension Study                     Long-Term Follow-Up Study


              ACUTE                         TAPER       LONG TERM OUTCOME
             BENEFIT                       (3 Weeks)       ASSESSMENT
             (6 Weeks)                                       (6 Months)


                            Transition from                    Antidepressant medication
                                    TMS to                 monotherapy w/TMS rescue as
                           pharmacotherapy             add-on if needed through 6 Months
Janicak, et al. Brain Stimulation, 2010.
Long Term Follow Up After Acute Treatment

 • Safety confirmed during long term, open-label 6 month
   follow up period
 • During open-label follow up on antidepressant
   medication monotherapy,
         – ~37% of patients required TMS reintroduction
         – ~85% of patients who received TMS reintroduction benefited
 • Net incidence of illness relapse under these open-label
   follow up conditions: 11%
         – Six-month relapse with antidepressant treatment alone in
           STAR*D study was 35-50% (Level 2 and 3 range)
Janicak, et al. Brain Stimulation, 2010.
The story of Geraldine…




 IDS-SR




CGI -S



  Photos used with patient’s permission
Learning points I hope we have
              achieved…
• Precise diagnosis.
• Improved concepts of ADHD presentation in
  children and adults.
• Avoid obvious drug-drug interactions.
• Avoid excess/inappropriate BZD’s.
• Avoid over-use of SGA’s.
• Understand TMS and where it fits into
  current psychiatric treatments
Contact information:
                Louis B. Cady, M.D.
              www.cadywellness.com

  www.indianaTMS-cadywellness.com

                 Office: 812-429-0772
     E-mail: lcady@cadywellness.com
        4727 Rosebud Lane – Suite F
                 Interstate Office Park
        Newburgh, IN 47630 (USA)
Scratching Your Head Psychiatry II: How to Practice INSIDE the Allopathic Box

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Scratching Your Head Psychiatry II: How to Practice INSIDE the Allopathic Box

  • 1. SCRATCHING YOUR HEAD PSYCHIATRY II: How to Think INSIDE the Allopathic Box… [and Practice Precisely, Effectively, and to Maximum Benefit] Louis B. Cady, MD – CEO & Founder – Cady Wellness Institute Adjunct Assoc. Professor – Indiana University School of Medicine Department of Psychiatry Child, Adolescent, Adult & Forensic Psychiatry – Evansville, Indiana (c) 2012 Louis B. Cady, M.D. - all rights reserved
  • 2. “Slumber not in the tents of your fathers. The world is advancing. Advance with it.” - Giuseppe Mazzine
  • 3. Relevance for your practice • ALL PRESCRIBERS - don’t kill your patient with a drug-drug interaction. • ALL PARTICIPANTS - Know bad/stupid psychopharmacology when you see it. – Be able to DO SOMETHING about it. • Don’t diagnose someone as having “drug problems” when they DON’T. • Better “MOA” understanding
  • 4. A quick look back in history The Interpretation of Ugo Cerletti 1935 Prozac - 1987 Dreams – 1885 - 1890
  • 5. The Therapeutic Trifecta of Psychiatry: Shrinking Shocking or Drugging [Supposedly the only three things you could do to a patient’s brain…]
  • 6. Dangers with Psychiatry/psychotropics • Failure to diagnose – (E.g “head case” and then they die of a medical problem) • Failure to adequately treat • Failure to prescribe accurately (Rx-rx interaction) • Giving people side effects • Using the wrong drug • Ignorance about best options because “I always did it that way.” • Getting people addicted • Practicing beyond your ability and expertise • Violating black box warnings
  • 7. *ACCURATE MEDICAL diagnosis a malpractice suit Depression & Anxiety & “mood disorder due to a in 1 Easy Lesson general medical condition” AND r/o bipolar disorder DEPRESSION Gen. ANXIETY D.O. SIG: E- CAPS! •Somatic Sx (“energy”,etc.) • Sleep •WORRY • Sadness •Irritability • Interest loss •Concentration • Guilt •Keyed up • *Energy •Insomnia (“sleep”) • Concentration •Restlessness • Appetite BEWARE BEWARE – “too much” • Psychomotor Sx energy • Suicidal thinking SWICKIR is Quicker: Worry + 3 = GAD (Baughman) 5of 9 with 1 of 2 x 2 weeks
  • 8. Lifetime Prevalence of Common Psychiatric Disorders Major depressive disorder 17.1% Alcohol dependence 14.1% Social anxiety disorder 13.3% PTSD 7.8% Generalized anxiety d.o 5.1% PMDD 5%* Panic disorder 3.5% OCD 2.5% 0 2 4 6 8 10 12 14 16 18 Lifetime prevalence (%) *In menstruating women. Kessler 1994; Kessler 1995; DSM-IV-TR™ 2000.
  • 9. Epidemiology of Depression Prevalence of Major Depression 20 point prevalence (30 day) 15 lifetime prevalence Percent 10 of Patients 5 0 Epidemiologic National Comorbidity Catchment Area (ECA) Survey (NCS) Regier et al., 1988; Blazer et al., 1994
  • 10. PHQ-9 Symptom Checklist More Nearly 1. Over the last 2 weeks, how often have you Not Several than half every been bothered by the following problems? at all days the days day 0 1 2 3 a. Little interest or pleasure in doing things     b. Feeling down, depressed, or hopeless     c. Trouble falling or staying asleep, or sleeping too much     d. Feeling tired or having little energy     e. Poor appetite or overeating     f. Feeling bad about yourself, or that you are a failure…     g. Trouble concentrating on things, such as reading…     h. Moving or speaking so slowly…     i. Thoughts that you would be better off dead…     Subtotals: 3 4 9 TOTAL: 16 Kroenke 2001.
  • 11. Depression—Impact on the Healthcare System • Compared with those without depression, depressed individuals: – Utilize all types of healthcare services more often – Incur 1½ to 2 times greater healthcare costs – increased length of hospital stay – significant worsening of physical, social, and role functioning Simon 1995; Luber 2000; Verbosky 1993; Wells 1989.
  • 12. Comorbidity of Depression and Anxiety Disability % Patients Disabled 3+ Days GAD + MDD 33.7% MDD/no GAD 19.45% GAD/no MDD 16.9% no GAD/no MDD 3.1% 0 5 10 15 20 25 30 35 40 45 Percent of Patients With ≥1 Disability Day in Past Month Wittchen, Depress Anxiety, 2002
  • 13. Where does ADHD come from?
  • 14. Kids and Adults – Differences in HYPERACTIVE domain AS A CHILD: AS AN ADULT: • Squirming, fidgeting • Work inefficiencies • Cannot stay seated • Can’t sit through meetings • Cannot wait turn • Cannot wait in line • Runs/climbs excessively • Drives too fast • Cannot play quietly • Self-selects very active job • On the go/driven by motor • Cannot tolerate frustration • Talks excessively • Talks excessively • Blurts out answers • Makes inappropriate • Intrudes, interrupts others comments • Interrupts others Sources: DSM-IV (TR). APA 2000:85-93) Weiss MD, Weiss JR. J Clin Psychiatry 2004;65(Suppl 3):27-37.
  • 15. Horrigan J, et al. Presented at 47th Annual AACAP Meeting: October 24-29, 2000. New York, NY.
  • 16. Persistence of ADHD Into Adulthood • ADHD is a heterogeneous disorder associated with considerable disability and comorbidity that, in many cases, persists into adulthood1 – Some studies have found persistence as high as 36.3% 2 • Mood, anxiety, and substance use disorders are the most common comorbid disorders in adults with ADHD 3 • Current prevalence of ADHD persistent into adulthood 4.4%4 (5% by new study – Willcut – Neurotherapeutics 2012 • Much of the treatment of adult ADHD can be based on experience in treating children/adolescents5 1. Barkley et al. J Abnorm Psychol. 2002;111:279-289. 2. Kessler RC et al. Biol Psychiatry 2005 June;57(11):1442-51. [retrospective review of 3,197 14-44 yo respondents in NCS-R] 3. Biederman et al. Am J Psychiatry. 1993;150:1792-1798. 4. Kessler et al. Am J Psychiatry. 2006;163(4):716- 23. 5. Dodson WW. J Clin Psychol. 2005;61:589-606.
  • 17. Diagnostic Pearls - Cady • How’s work? – How has your employment history been? • How’s your mood? Your marriage (relationship)? • How was school for you? • Are people nervous driving with you? • Are there periods of time when you have too much energy for no particular reason? • Do you ever have to have a beer at the end of the day to relax? – [gently lead in to other substances, especially stimulants that may have a CALMING effect] – “Have you ever taken any of your child’s ADD Rx?” [or other stimulants, energy drinks, diet pills, or cocaine]
  • 18. Pharmacology Failures… 1. “Begin with the end in mind.” (Covey) 2. Start LOW – (rule of thumb – ½ what the drug rep and package insert says!) 3. Go up to the maximum tolerated dosage, with finesse. – Tell them about “Goldilocks” 1. If it doesn’t work, add something complimentary (that makes sense).
  • 19. THE FACTS • SSRI’s treat depression AND/OR anxiety • Patients may INITIALLY need something else for daytime anxiety or sleep. • BZD’s of choice: – clonazepam 1 mg tablets – ½ to 1 twice daily to three times daily – Diazepam – 5 mg =- ½ - 1 ½ twice daily to three times daily • (first pass and second pass effects) • ANTIANXIETY RX (non BZD) – Buspirone, per package insert. Push to 20 mg THREE TIMES DAILY or to the point of maximum tolerability for 4 – 6 weeks AT THAT DOSE. – Start with 5 mg. Can use WITH SSRI’s
  • 20. AVOID Alprazolam (Xanax ®) • Addicting (and rapidly so) • Can have seizures if rapidly withdrawn (structurally similar to carbamazepine) • MD’s shot over it. • NOT an “anti-anxiety” medication • NOT a sleeper. • Even if they need a BZD for anxiety, it doesn’t have to be Xanax.
  • 21. Sleepers – my preferences • Rozerem (brand) (a melatonin analog) – 8 (up to 16* mg) at bedtime. VASTLY under-rated. May need to take 2 weeks before adequate effect. (* off-label dose) – Dual acting agent – homeostatic and circadian effects. 70x as potent as melatonin. – Melatonin SR may also be a good agent. • Trazodone (50 – 150mg ½ - 2 hrs before HS. (Note, off label “unapproved.” Warn on priapism). • Lunesta (brand) – 2 – 3 mg. Try samples. Have mouthwash on hand. (Probably most predictable agent) • Ambien 12.5 mg CR (brand) – legitimately lasts longer than zolpidem. Probably not as effective as Lunesta. • Zolpidem – generic. People get hooked on it. • Paradigm: SYMPTOMATIC treatment – after depression is stabilized, fade out the sleeper
  • 22. Why treatment failures occur: too much or too little… The REAL mechanism of action of SSRI’s Animation © NEI, Inc. (Neuroscience Institute) and is used specifically with permission from Stephen Stahl, MD, Ph.D.
  • 24. Depression/anxiety Rx: • TCA • Venlafaxine (Effexor) • Duloxetine (Cymbalta) • Mirtazapine (alpha 2) • Desmethylvenlafaxine (Pristiq) & others….
  • 25. Side Effects & Drug Interactions: The Doc Cady “Can’t s” of the TCA’s Pee ANTICHOLINERGIC/ Poop ANTIMUSCARINIC Spit EFFECTS Spurt Focus Think  Stand up Alpha-adrenergic  Stay awake blockade  Stay thin "Antihistamine" effects
  • 26. “Drug-drug interactions” clinically relevant?!
  • 27. Drug-drug interactions: chum for legal “sharks”
  • 28. “Strattera [coupled with Prozac or Paxil] has been great for our admissions. ” -Dr. William Beute, MD Pine Rest Campus Clinic Grand Rapids, MI April 21, 2004 [quoted with permission]
  • 29. Cytochrome p-450 2D6 inhibition measured as % increase in “Desipramine AUC” – in vivo data Critically important when combining with other Rx metabolized through 2D6 pathways Preskhorn, Alderman, et al. Pharmacokinetics of desipramine coadministered with sertraline or fluoxetine. J. Clin Psychopharmacol 1994;14:90-98; Escitalopram package insert - note – different source of data, but same method
  • 30. Some drugs metabolized through cytochrome P-450 IID6 system ADHD Antibiotics ANTI-PAIN Amphetamines •TMP & SMX STRATTERA CODEINE! •Ampicillin Analgesics •Erythromycin Bronchodilators •Acetaminophen •Penicillin •Theophylline •Aspirin •Tetracycline Cardiac Antacids Antidepressants •Digoxin; digitalis Antiarrthymics •TCA’s & “2P’s” Cough •Procainamide, Antihistamines •Dextromethorphan •Quinidine Antihypertensives Diuretics •Encainide •Flecainide Antipsychotics •Chlorthalidone Anticonvulsant •Clozaril •Furosemide •carbamazepine •Risperdal •HCTZ •Zyprexa •Triamterine
  • 31. The “not so selective” SSRI’s; how to “Do yourself a favor.” drug SSRI? 2nd order effects Side effects possible Escitalopram Yes NOTHING (excess serotonin side (Lexapro) now effects only) generic Sertraline (Zoloft) Yes Dopamine (1/3 as Agitation, nervousness; potent as improved [ ] amphetamine) Citalopram Yes AntiH1 Sedation (note- FDA (Celexa) lowered max dose to 40mg) Paroxetine (Paxil) Yes Ach Doped up, TCA effects, NOT “NRI” neurocognitive problems, withdrawal. Sexual, Prostate sxs Fluoxetine Yes 5HT2C Agitation, appetite (Prozac) suppression
  • 32. New Agents, New Mechanisms (agent) (MOA) Differentiating points Venlafaxine (“IR” and XR) SSRI, NRI Nausea, GI side effects, sxl (Effexor) dysfunction Duloxetine (Cymbalta) SSRI, NRI Same. Better tolerated. For pain w/ dep. Desvenlafaxine (Pristiq) – SSRI, NRI Better tolerated “son of Effexor” Trazodone XR with 5HT2a/c Legitimate effect on Contramid® (OLEPTRO) BLOCKER, mild depression/anxiety without SSRI doping up. Vilazodone (Viibryd) SPA, SSRI ONLY SPARI. Weaker “SSRI.” Targets 5HT1A. Less sexual side effects. Bupropion (“XL” – not “NDRI” Possibility of anxiety & “wound “SR”) (Wellbutrin) up.” Improved concentration. Push to 450 mg. SZ warning..
  • 33. An illustrative study on picking your antidepressant… Duloxetine (Cymbalta) Versus Escitalopram (Lexapro) and Placebo: An 8-month, Double-Blind Trial in Patients With Major Depressive Disorder Pigott et al., Curr Med Res Opin, 2007
  • 34. Retardatio Comparison of Escitalopram and Duloxetine: HAMD (MMRM) 8-Month Trial 17 Maier Subscales Sleep * Somatization Anxiety/ Total Score *p<0.05 Pigott et al., Curr Med Res Opin, 2007
  • 35. Comparison of Escitalopram and Duloxetine: 8- Month Trial Significantly Different Adverse Events (p<0.05 Duloxetine vs Escitalopram) Percent of Patients Pigott et al., Curr Med Res Opin, 2007
  • 36. Comparison of Escitalopram and Duloxetine: 8-Month Trial Conclusions: they both worked the same; side effects were worse with duloxetine • Remission rates for both escitalopram and duloxetine continued to improve over time • Significantly more escitalopram-treated patients continued treatment compared to duloxetine-treated patients • Escitalopram showed significant improvement vs duloxetine on the HAMD17 sleep subscale • Compared to escitalopram, duloxetine significantly increased pulse and systolic blood pressure Pigott et al., Curr Med Res Opin, 2007
  • 37. Two New Agents You Need to Know • Extended release Trazodone – NOT “son of Trazodone” – Possibility of legitimate antidepressant effect with anti- anxiety effect WITHOUT doping patient up. – A “SARI” – serotonin antagonist reuptake inhibitor • Vilazodone – the only SPARI available. • How to appreciate: – 5HT1A is receptor for antidepressant effect of serotonin – 5HT2A and 5HT2 C: anxiety, sleep disruption, sexual side effects. – ANYTHING which works preferentially on 5HT1A is GOOD!
  • 38. XR Trazodone steady state dosing study • (Levels done after 7 days steady state) • 300 mg XR Traz AUC comparable to 100 mg IR Traz tid • Cmax 42% lower than IR Trazodone – Translation – it doesn’t dope the patient up. Kramer, WG et al. Once-daily Trazodone: Overview of Pharmacokinetic Properties. Poster – ACCP 38th Annual Meeting, San Antonio, TX 2005
  • 39. XR Trazodone Food Effect Study • PI says “take at night” • CMax increase by 86% (!!!) under fed conditions. Peak is at 7 hours post dose (with feeding). • Note – this may lead the enlightened prescriber to vary the time of dosing. Kramer, WG et al. Once-daily Trazodone: Overview of Pharmacokinetic Properties. Poster – ACCP 38th Annual Meeting, San Antonio, TX 2005
  • 40. Vilazodone – a SPARI (per Stephen Stahl, MD, Ph.D.) – Serotonin Partial Agonist Reuptake Inhibitor • Highly serotonergic. START LOW (5 mg). • Because of 5HT1A agonism, LESS “SSRI” effect is required.
  • 41. ADHD Rx for frontline medicine • Desiderata – get control, and keep it consistent for predictable period of time • Rules of thumb: don’t be guided on SIZE. START LOW. “Know the Biederman max” for MPH and amphetamine. • Recommendations (for children and adult): – Focalin XR (Dexmethylphenidate XR) 5,10,15,20,30 and 40 mg capsules) • Rationale: MPH based. FAST. 8 – 10 hours. Can dose twice daily (off- label), a.m. >pm. (can also start with ½ capsule) – Vyvanse – (lisdexamfetamine [sic]) – 20,30,40,50,60,70 mg [= 7.5 – 30 mg] amphetamine equivalents. Lasts 12 – 14 hours. (Can dissolve in water – per PI!). – Kapvay/Intuniv – FDA approved in kids. • Kapvay easier to use, better tolerated. • Intuniv more potent, but more side effects (sedation)
  • 42. Practicing beyond your ability (and knowledge) – the second generation antipsychotics • Definitions: – Mood stabilizer – something that stabilizes mood (Lithium, carbamazepine, VPA) – Antipsychotic – something you give someone who is PSYCHOTIC to get them UNPSYCHOTIC. – Antidepressant – something for depression. – “2nd generation antipsychotic (“SGA’s”) = S2/D2 blockers.” • Can “stabilize mood” as well as function as antipsychotics • Now some FDA approved for either add-on use or single agents for “bipolar depression” (e.g., quietapine XR)
  • 43. Know who you’re playing with • SGA’s and WEIGHT GAIN (Cady experience) – olanzapine/risperidone > quietapine> aripiprazole/arsenapine> lurasidone/ziprasidone • (Zyprexa/Risperdal>Seroquel> Abilify/Saphris> Latuda/Geodon) • EXPENSIVE: $400 – $600 /per month • All will work for mania. NONE are pure “mood stabilizers.” Some make you fat. • Some will work for depression but dope you up. • Much less risky than 1st generation for tardive dyskinesia. • Axiom: refine your psychopharmacology before going to look for an SGA. • If you have to use one (for bipolar or psychosis, Lurasidone is probably most benign – 40 – 80 mg twice daily (or 160 mg HS)
  • 44. Cady recommendation for SGA’s in primary care • As little as possible. • Do NOT use as primary mood stabilizers for bipolar disorder. Use lithium (Type I) VPA (Type I/II) or Lamotrigine – which is a real option. Check levels and labs as needed • Can use if single, or better yet, DOUBLE mood stabilizers don’t work. • Abilify (only “dopaminergic” SGA) probably best for antidepressant augmentation at LOW DOSE. – 2 – 4 or 5 mg is optimum dose for this. (Start with ½ of a 2 mg and go up) – Onset is FAST when it happens. • Olanzapine is most dependable for rapid onset and control of manic episode, or agitation, or EXTREME PANIC & anxiety (off label).. Lurasidone may be best tolerated.
  • 45. A quick look back in psychiatric tx: The Interpretation of Ugo Cerletti 1935 Prozac - 1987 Dreams – 1885 - 1890
  • 46. The Therapeutic Trifecta of Psychiatry: Shrinking Shocking or Drugging [Supposedly] the only three things you could do to a patient’s brain…]
  • 47. STAR*D Study demonstrates that current treatment has limited effectiveness 47 Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Psychiatry; McGrath (2006) Am J Psychiatry
  • 48. Likelihood of discontinuing treatment increases with each new medication attempt Systemic Drug Side Effects  Weight Gain  Fatigue  Constipation  Headache/ Migraine  Diarrhea  Abnormal  Nausea Ejaculation  Drowsiness  Impotence  Insomnia  Sweating  Decreased  Tremor Libido  Treatment  Nervous Discontinuati Anxiety on Side Effects  Increased Appetite  Weakness  Decreased  Dry Mouth Trivedi (2006) Am J Psychiatry; Rush (2006) Am J Psychiatry; Fava (2006) Am J Appetite Psychiatry; McGrath (2006) Am J Psychiatry; Neuronetics, Inc. (data on file)  Dizziness
  • 49. ECT – origins • Origin in 1700’s – Middlesex Hospital – machine with weak electrical current used for range of illnesses. – John Birch, English neurosurgeon, used it to shock the brains of depressed patients – Benjamin Franklin, after shocked, recommended electric shock for tx of mental illness • Ugo Cerletti – 1935 – noted (incorrectly) that epilepsy and schizophrenia didn’t occur in same patient • Problems with ECT – memory loss, anesthesia risk • Cost of $6400 for eight treatments • 80% improvement • 33,000 hospitalized Americans – ECT in 1980, last year for NIMH figures – http://www.faqs.org/health/topics/19/Electroconvulsive-therapy.html
  • 50. But even before Freud… • Electromagneitc induction – 1831 (Michael Faraday & Joseph Henry) • 1st demonstrated by Faraday August 29, 1831
  • 51. Faraday’s Law of Induction TMS Induced neuronal Magnetic current field
  • 52. From electricity to magnetism • Bartholow, R (1874) – Stimulation of human brain (exposed cortex) of patient with cranial defect. • d’Arsonval – “Phosphenes and vertigo” induced inside powerful magnetic coil • Silvanus P. Thomson, Ph.D. – new type of magnetic Thompson, SP. “A Physiological Effect of an Alternating Magnetic stimulation (1910) Field.” Proceedings of the Royal Society of London B82:396-399, 1910
  • 53. First patent application for magnetic therapy: • 1902 Adrian Pollacsek and Berthold Beer – Vienna, Austria for a “therapeutical apparatus” • Electromagnetic coil, placed over the skull was noted to “pass vibrations into the skull” and “treat depression and neuroses.”
  • 54. A quick look back in psychiatric history - redux Shrinking Zapping Shocking Drugging Freud: The Silvanus P. Ugo Cerletti 1935 Prozac - 1987 Interpretation of Thompson, Dreams – 1885 - Ph.D. (1910) 1890
  • 55. First modern TMS: • Barker AT, et al. “Non- invasive magnetic stimulation of the human motor cortex. The Lancet 1:1106-1107, 1985. • 1st device – designed by Barker – Univ. of Sheffield, England. – 100 microsecond, 2 T pulse
  • 56. Coil types and rationale From Matt Edwardson, MD – Research Fellow and Acting Instructor, Dept. of Neurology, Univ. of WA 10/16/2011
  • 57. An unusual side effect of imaging (2004)… • CONCLUSIONS: “These preliminary data suggest that the EP-MRSI scan induces electric field that are associated with reported mood improvement in subjects with bipolar disorder.”
  • 59. NeuroStar TMS Directly Depolarizes Cortical Neurons Neuron Pulsed magnetic fields from NeuroStar: •induce a local electric current in the cortex which depolarizes Neurons are neurons “electrochemical •eliciting action potentials cells” and respond to •causing the release of either electrical or chemical stimulation chemical neurotransmitters
  • 60. NeuroStar Releases Neurotransmitters in the Brain These effects Depolarization of neurons in the DLPFC causes local are associated neurotransmitter release with improvements in Dorsolateral prefrontal depressive cortex symptoms Anterior cingulate cortex Kito (2008) J Neuropsychiatry Clin Neurosci Depolarization of pyramidal neurons in the DLPFC also Activation of deeper brain causes neurotransmitter release neurons then exerts secondary in deeper brain neurons effects on remaining portions of targeted mood circuits
  • 61. ECT TMS Anesthesia, LOC ECT vs. TMS No Yes Induction of seizure Yes No Systemic effects Anesthetic drugs, none increase HR Treatment schedule 3X/ week (8 -15 tx) Daily, M-F, six weeks (30 tx) Rapidity of onset 2 – 3 treatments 2 – 3 weeks Mechanism of action SEIZURE. Massive NT Precise, LOCAL release release; rise in sz of NT’s. Reactivation of threshold neural circuits. Side effects Memory loss, confusion Essentially none (mild HA 1st week) Psychosocial impact can’t work Drive to and from tx’s, work improved After-effects Mild (usually transient) None. Pro-cognitive memory loss Insurance coverage Almost always Rare. Improving
  • 64. Does it work? • Original registration trial – 307 major depressed patients • 67% women • 93% recurrent depressives • 43% had been hospitalized already – 42 sites – Treatment per label • Results: ½ patients responded; 1/3 of patients remitted. • 80% patients completed the treatment.
  • 65. Who Was Studied? • Primary diagnosis: DSM-IV Major Depressive Disorder – Unipolar type, non-psychotic – Moderate to severe symptoms at baseline – Approximately one-third of patients had a co-morbid anxiety disorder (OCD excluded) • Antidepressant Treatment History: – Average number of antidepressant medication trials in current episode = 4 (range: 1 to 23 attempts) • Majority of treatment attempts were unable to achieve adequate dose and duration of treatment due to intolerance – In the indicated patient population, all patients failed to achieve satisfactory benefit from one antidepressant medication at an adequate dose and duration in current episode 65 Demitrack and Thase (2009) Psychopharm Bulletin
  • 66. O’Reardon, JP, et al. (2007) Efficacy and Safety of Transcranial Magnetic Stimulation in the Acute Treatment of Major Depression: A Multi-Site Randomized Controlled Trial. Biol Psychiatry 62:1208-1216.
  • 67. Optimization of TMS (‘OPT-TMS’) Study Mark S. George, MD; Sarah H. Lisanby, MD; David Avery, MD; William M. McDonald, MD; Valerie Durkalski, PhD; Martina Pavlicova, Phd; Berry Anderson, Phd, RN; Ziad Nahas, MD; Peter Bulow, MD; Paul Zarkowski, MD; Paul E. Holtzheimer III, MD; Theresa Schwartz, MS; Harold A. Sackeim, PHD Major Findings: • NIMH-funded, independent of industry • MADRS total score decreased:16.6% • N=190 patients, 4 premier academic sites (Active) vs 6.9% (Sham) p=0.01 • Primary outcome measure: (Effect size: 0.51) % Remission - Active 15% vs Sham 4% (P = • 30% of patients achieved remission 0.015); Odds Ratio of achieving remission: in open-label extension phase 4.2 (95%CI, 1.3-13.2) • Excellent safety and adherence Conclusion: “Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham.”
  • 68. Recent TMS Literature Review • Roughly 30 controlled clinical research studies to date • Most recent meta-analysis (Slotema, et al, 2010): – Included analysis of 34 studies involving 1,383 patients – Estimated standardized effect size = 0.55 (P < 0.001) Conclusion: “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression…and has a mild side effect profile….” 1.Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)J Clin Psych 71(7):873-84. 2.Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine, 39:65-75.
  • 69. NeuroStar TMS Therapy: Safety Overview • No systemic side effects • No adverse effect on cognition • Most common adverse event associated with treatment was scalp pain or discomfort – < 5% of patients discontinued due to adverse events • No seizures with NeuroStar device during clinical studies (over 10,000 treatments) • Rare risk of seizure with NeuroStar TMS in post-market use (0.003% per treatment, <0.1% per acute treatment course) (>150,000 treatments in post-marketing experience to date) • Long term safety demonstrated in 6 months follow-up Janicak, et al. J Clin Psychiatry, 2008; Janicak, et al. Brain Stimulation, 2010.
  • 70. No Evidence of Emergent Suicidal Ideation 4.0 NeuroStar TMS Therapy (n=155) HAMD Item 3 Suicidal Ideation 3.5 Sham TMS (n=146) 3.0 Shift Score (%)* 2.5 2.0 1.5 1.0 0.5 0.0 Baseline Week 2 Week 4 Week 6 * Shift Score indicates the percent of subjects who experienced a change in HAMD Item 3 score from 0 or 1 at baseline to 3 or 4 at later point in time. Janicak (2008) J Clinical Psychiatry.
  • 71. Long Term Follow Up After Acute Treatment RCT or Open-Label Extension Study Long-Term Follow-Up Study ACUTE TAPER LONG TERM OUTCOME BENEFIT (3 Weeks) ASSESSMENT (6 Weeks) (6 Months) Transition from Antidepressant medication TMS to monotherapy w/TMS rescue as pharmacotherapy add-on if needed through 6 Months Janicak, et al. Brain Stimulation, 2010.
  • 72. Long Term Follow Up After Acute Treatment • Safety confirmed during long term, open-label 6 month follow up period • During open-label follow up on antidepressant medication monotherapy, – ~37% of patients required TMS reintroduction – ~85% of patients who received TMS reintroduction benefited • Net incidence of illness relapse under these open-label follow up conditions: 11% – Six-month relapse with antidepressant treatment alone in STAR*D study was 35-50% (Level 2 and 3 range) Janicak, et al. Brain Stimulation, 2010.
  • 73. The story of Geraldine… IDS-SR CGI -S Photos used with patient’s permission
  • 74. Learning points I hope we have achieved… • Precise diagnosis. • Improved concepts of ADHD presentation in children and adults. • Avoid obvious drug-drug interactions. • Avoid excess/inappropriate BZD’s. • Avoid over-use of SGA’s. • Understand TMS and where it fits into current psychiatric treatments
  • 75. Contact information: Louis B. Cady, M.D. www.cadywellness.com www.indianaTMS-cadywellness.com Office: 812-429-0772 E-mail: lcady@cadywellness.com 4727 Rosebud Lane – Suite F Interstate Office Park Newburgh, IN 47630 (USA)

Editor's Notes

  1. Giuseppe Mazzini (22 June 1805 – 10 March 1872), nicknamed &quot;Soul of Italy,&quot;[1] was an Italian politician, journalist and activist for the unification of Italy. His efforts helped bring about the independent and unified Italy[2] in place of the several separate states, many dominated by foreign powers, that existed until the 19th century. He also helped define the modern European movement for popular democracy in a republican state. [ citation needed ] – Source - Wikipedia
  2. 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.
  3. As demonstrated by this chart, psychiatric disorders are prevalent. 1-3 These data are from the National Comorbidity Survey (NCS) and the DSM-IV-TR ™ . The NCS is a collaborative epidemiologic investigation based on household survey data of over 8000 respondents from 1990 to 1992. 4
  4. Depression can strike anyone at any age, but on average it begins in the late 20s. Depressive illness is a highly prevalent disorder associated with substantial morbidity and mortality. According to the World Health Organization, major depression is the leading cause of disability in the U.S. and worldwide. The annual costs associated with depression (both direct and indirect) in the U.S. were estimated to be $43.7 billion in 1990. Epidemiologic studies suggest that in any 30-day period, 2 to 5 percent of the U.S. population meet criteria for major depression. The lifetime probability of experiencing a major depressive episode has been estimated to be as high as 17 percent. Nearly twice as many women (21%) as men (13%) are affected by a depressive disorder during their lifetimes. References 1. Murray CJL, Lopez AD, eds. Summary: The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020. Cambridge, MA: Published by the Harvard School of Public Health on behalf of the World Health Organization and the World Bank, Harvard University Press; 1996. 2. Regier DA, Boyd JH, Burke JD Jr, Rae DS, Myers JK, Kramer M, Robins LN, George LK, Karno M, Locke BZ. One-month prevalence of mental disorders in the United States: based on five Epidemiologic Catchment Area sites. Arch Gen Psychiatry. 1988; 45:977-986. 3. Blazer DG, Kessler RC, McGonagle KA, Swartz MS. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am J Psychiatry . 1994;151:979-986. 4. Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50(2):85-94. Kessler RC, McGonagle KA, Swartz M, Blazer DG, Nelson CB. Sex and depression in the National Comorbidity Survey I: lifetime prevalence, chronicity and recurrence. J Affect Disord. 1993;29:85-96. Greenberg PE, Stiglin LE, Finkelstein SN, Berndt ER. The economic burden of depression in 1990. J Clin Psychiatry . 1993;54:405-418.
  5. The PHQ-9 symptom checklist asks the patients in a self-report format, “ Over the last 2 weeks, how often have you been bothered by the: following problems? Little interest or pleasure in doing things; feeling down, depressed or hopeless; trouble falling or staying asleep or sleeping too much; feeling tired or having little energy; poor appetite or overeating; feeling bad about yourself or that you are a failure; trouble concentrating on things; moving or speaking slowly; thoughts that you might be better off dead. ” These are all depression DSM-IV-TR items. Patients can score for themselves how often they have experienced these individual symptoms. 37
  6. In addition to utilizing services related to their depression, patients also tend to be high utilizers of general medical care services. It has been shown that depressed patients utilize all types of healthcare services more often than nondepressed patients and incur overall healthcare costs 1 ½ to 2 times higher than the average nondepressed patient. 27,28 It has also been demonstrated that depressed individuals were hospitalized longer and had significant worsening of physical, social, and role functioning, compared with nondepressed individuals. 28-30
  7. Both MDD and GAD are associated with considerable functional impairment and disability. Comorbid depression and GAD tends to result in greater levels of disability as measured by the proportion of patients who report 1 or more days of disability in a 30-day period. Patients experience diminished functioning both at work and socially, with many reporting moderate or severe social disability. Reference Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety . 2002;16:162-171.
  8. ADHD is a heterogeneous disorder associated with considerable disability and comorbidity that, in many cases, persists into adulthood. 1 Mood, anxiety, and substance use disorders are the most common comorbid disorders in adults with ADHD. 2 ADHD in adults is more prevalent than once thought. The National Comorbidity Survey found the estimated lifetime prevalence of ADHD in adults to be 8.1%. 3 According to DSM-IV criteria, adults diagnosed with ADHD must have had childhood onset and persistent and current symptoms, although allowance is made for partial remission. 4 Due to the great syndromatic continuity between childhood and adult ADHD, much of the medication management of adults with ADHD can be based on the experience gained from treating children and adolescents. 5 Barkley RA, Fischer M, Smallish L, Fletcher K. The persistence of attention-deficit/hyperactivity disorder into young adulthood as a function of reporting source and definition of disorder. J Abnormal Psychol. 2002;111:279-289. Biederman J, Faraone SV, Spencer T, et al. Patterns of psychiatric comorbidity, cognition, and psychosocial functioning in adults with attention deficit hyperactivity disorder. Am J Psychiatry . 1993;150:1792-1798. Kessler RC, Berglund P, Demler O, Jin R, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry . 2005;62:593-602. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders . 4th ed. ( DSM-IV  ). Washington, DC: American Psychiatric Association; 1994:78-85. Dodson WW. Pharmacotherapy of adult ADHD. J Clin Psychol . 2005;61:589-606.
  9. In a flexible dose study evaluating the safety and efficacy of escitalopram in the treatment of panic disorder (with or without agoraphobia), outpatients were randomized to receive placebo, citalopram or escitalopram. There were approximately 120 patients per treatment group. Following a 2-week single-blind lead-in period, patients received 10 weeks of double-blind treatment. Treatment was initiated at a low dose (10 mg/day for citalopram and 5 mg/day for escitalopram) and then titrated after one week to 20 mg/day for citalopram and 10 mg/day for escitalopram. After week 4, dose could be increased to 40 mg/day citalopram and 20 mg/day citalopram. The Panic and Anticipatory Anxiety Scale (PAAS) and the Panic and Agoraphobia (P&amp;A) scale were used to quantify panic attacks, anticipatory anxiety, and phobic avoidance.
  10. Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin. 2007 Apr 27;
  11. Overall effects of treatment of depression were assessed by the HAMD 17 total score using MMRM analysis. Treatment effects related to the somatic symptoms associated with depression were assessed by the anxiety/somatization subscale that consists of HAMD 17 items 10 (psychiatric anxiety), 11 (somatic anxiety), 12 (gastrointestinal-related symptoms), 13 (general somatic symptoms), 15 (hypochondriasis), and 17 (insight). The sleep subscale (HAMD 17 items 4, 5, and 6) was used to assess the treatment effects on insomnia (initial, middle, and terminal). The Maier subscale measures the core symptoms of depression and comprises HAMD 17 items 1 (depressed mood), 2 (feelings of guilt), 7 (work and activities), 8 (retardation), 9 (agitation), and 10 (psychic anxiety). The impact of treatment on energy and interest levels was evaluated by the retardation subscale: HAMD 17 items 1 (depressed mood), 7 (work and activities), 8 (retardation), and 14 (genital symptoms). After 8 months of treatment, duloxetine (60-120 mg/day) and escitalopram (10-20 mg/day) showed similar efficacy on HAMD 17 total and subscale scores, except the sleep subscale. On the HAMD 17 sleep subscale, escitalopram was significantly more efficacious than duloxetine (p&lt;0.05). Rates of remission were not significantly different between escitalopram and duloxetine over the 8-month course of the study (50% vs 47%; respectively). Because so few patients on placebo (n=15) completed the entire 8-month study, the power to detect a difference between placebo and active treatments after 8 weeks was significantly decreased and very likely to be insufficient. Reference Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM. Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin . 2007;23(6)1303-1318.
  12. This slide shows the adverse events that were significantly different between escitalopram and duloxetine. Nausea, dry mouth, vomiting, yawning, and night sweats were reported at a significantly higher rate with duloxetine than with escitalopram, whereas only migraine was more frequently reported in the escitalopram group than in the duloxetine group. References: Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM. Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin . 2007;23(6)1303-1318.
  13. Throughout this 8-month extension study, escitalopram and duloxetine showed similar efficacy on all study measures except on the HAMD 17 sleep subscale. On the HAMD 17 sleep subscale, escitalopram was significantly more efficacious than duloxetine. Remission rates between escitalopram and duloxetine were not significantly different and both treatments lead to continued improvement over time. Significantly more escitalopram-treated patients continued treatment compared to duloxetine-treated patients, and duloxetine treatment led to an increase in both pulse and systolic blood pressure. References: Pigott TA, Prakash A, Arnold LM, Aaronson ST, Mallinckrodt CH, Wohlreich MM. Duloxetine versus escitalopram and placebo: an 8-month, double-blind trial in patients with major depressive disorder. Curr Med Res Opin . 2007;23(6)1303-1318.
  14. 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.
  15. 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). &quot;A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report.&quot; Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). &quot;Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report.&quot; Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). &quot;A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report.&quot; Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). &quot;STAR*D: What have we learned?&quot; Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). &quot;Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report.&quot; Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). &quot;Medication Augmentation after the Failure of SSRIs for Depression.&quot; New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). &quot;Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice.&quot; Am J Psychiatry 163 (1): 28-40.
  16. 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). &quot;A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A Star*D Report.&quot; Am J Psychiatry 163 (7): 1161-1172. McGrath, P. J., J. W. Stewart, et al. (2006). &quot;Tranylcypromine Versus Venlafaxine Plus Mirtazapine Following Three Failed Antidepressant Medication Trials for Depression: A STAR*D Report.&quot; Am J Psychiatry 163 (9): 1531-1541. Nierenberg, A. A., M. Fava, et al. (2006). &quot;A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report.&quot; Am J Psychiatry 163 (9): 1519-1530. Rush, A. J. (2007). &quot;STAR*D: What have we learned?&quot; Am J Psychiatry 164 (2): 201-204. Rush, A. J., M. H. Trivedi, et al. (2006). &quot;Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report.&quot; Am J Psychiatry 163 (11): 1905-1917. Trivedi, M. H., M. Fava, et al. (2006). &quot;Medication Augmentation after the Failure of SSRIs for Depression.&quot; New England Journal of Medicine 354 (12): 1243-1252. Trivedi, M. H., A. J. Rush, et al. (2006). &quot;Evaluation of Outcomes with Citalopram for Depression Using Measurement-Based Care in STAR*D Implications for Clinical Practice.&quot; Am J Psychiatry 163 (1): 28-40. Product Labeling for currently marketed antidepressants (Neuronetics, Inc., data on file)
  17. Capacitors of the day did not permit high intensity or rapid frequency use. The “ phosphenes ” were either generate from effects on the occipital cortex or directly on the retina of the eye. 1959 – Kolin et al – first to demonstrate magnetic field could stimulation a peripheral frog muscle preparation.
  18. The underlying rationale for the use of TMS exploits the fact that neurons are electrochemical cells. This means that neuronal activity can be affected either chemically, via the use of drugs, or electrically, via interventions like TMS.   Unlike drug action, whose effects tend to be anatomically diffuse, the effects of TMS 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. The TMS device is a powerful electromagnet, which is turned on and off in a rapid fashion, producing a pattern of “pulsed” magnetic fields. When pulsed magnetic fields are positioned close to an electrical conductor, like neurons, a local electrical current is produced in that conductor. This electric current is powerful enough right under the magnetic coil to elicit action potentials, which then travel down the neuron, ultimately causing the release of neurotransmitters at the synapse (Post 2001, p. 193A) . References : Post A, Keck ME. Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? J Psychiatric Research. 2001;35: 193-215.
  19. When the pulsed magnetic fields from the TMS coil are applied to the left dorsolateral prefrontal cortex, there are a series of events that are thought to underlie the therapeutic effects of TMS in the treatment of major depression: First, direct neuronal depolarization under the coil leads to local action potentials in neurons and the local release of neurotransmitters in the cortex. In addition to these local effects, neuronal depolarization of cortical pyramidal neurons is thought to occur (as represented by the blue neural pathway), reaching to deeper brain regions that lie outside the direct action of the pulsed magnetic fields. Activation of these deeper brain regions is then presumed to lead to secondary activation of brainstem neurotransmitter centers, which are then presumed to result in upward influences on the remaining brain regions involved in mood regulation (represented by the purple neural pathway). As a result, dopamine (Kanno 2004, pp. 75A, 76A, 77A) and serotonin (Juckel 1999, pp. 393A, 394A) activity are increased in areas of the brain whose low neurotransmitter activity have been linked to depression. The activity may be increased both in the short term by increasing release of neurotransmitters and in the long term by modulating expression of proteins involved in neurotransmitters signaling (Post 2001, p. 200A,B). Presumably, as a result of these changes, depression lifts (Slotema 2010, p. 876A). The net action of TMS is therefore targeted on the specific brain areas known to be involved in the regulation of mood, and is comprehensive in that its action has both direct effects on local neurons in the cerebral cortex, and then results in deeper actions on brain regions that are distant from the site of stimulation, but neurally connected to these cortical areas. These effects can be demonstrated in human neuroimaging studies of patients who have undergone treatment with TMS for their depression, as shown in the SPECT (single photon emission computed tomography) scan on the right (Kito, et al, 2008). In this image, the TMS coil has been positioned over the dorsolateral prefrontal cortex on the left side of the head. The area just underneath the coil is showing increased metabolic activity as a direct result of the magnetic stimulation. You can also see that the increase in metabolism reaches secondarily the deeper brain regions, in this case the regions of the cingulate cortex also show increased activation. References : Kanno M, Matsumoto M, et al. Effects of acute repetitive transcranial magnetic stimulation on dopamine release in rat dorsolateral striatum. J Neurological Sciences. 2004;217:73-81. Juckel G, Mendlin MA, et al. Electrical Stimulation of Rat Medial Prefrontal Cortex Enhances Forebrain Serotonin Output: Implications for Electroconvulsive Therapy and Transcranial Magnetic Stimulation in Depression. Neuropsychopharmacology. 1999;21(3):391-398. Slotema CW, Blom JD, et al. Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A meta-analysis of the efficacy of rTMS in psychiatric disorders. J Clin Psychiatry. 2010;71(7):873-884. Kito, S, Fujita, K, Koga, Y. 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. 2008; 20(1):74-80.
  20. This slide describes some of the major demographic and clinical characteristics of the patients studied in the registration clinical trials that led to FDA clearance for the NeuroStar TMS Therapy system.   All patients had a diagnosis of unipolar, non-psychotic major depression, with moderate to severe symptoms at entry to the study. About a third of all patients had a concurrent secondary diagnosis of an anxiety disorder.   All patients received a rigorous characterization of their antidepressant medication treatment history in the current illness episode. Most patients had received numerous medication treatment attempts, with one of these treatment attempts being administered at an adequate daily dose and for at least four weeks without clinical benefit. The average number of overall treatment attempts (which includes all antidepressant medications administered in the current episode, regardless of whether they reached an adequate dose and duration) was 4, with a range across the study population from 1 to as many as 23 treatment attempts.   Consistent with the data that I reviewed earlier in this presentation, about 75% of the time, these antidepressant treatment attempts were unable to achieve this minimum level of exposure adequacy (usually because of treatment intolerance, or failure to adhere to the recommended treatment regimen).   References : Demitrack, MA , Thase, ME,. (2009) Clinical significance of transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant depression: synthesis of recent data. Psychopharm Bulletin 42(2) :5-38
  21. Subsequent to the FDA clearance of the NeuroStar TMS system, the second-largest, randomized, sham-controlled clinical trial examining the safety and efficacy of TMS in major depression has now been reported.   This study has been referred to as the Optimization of TMS Study, or ‘OPT-TMS’ by its investigators. It is a very important study for several reasons:   It was conducted independent of industry, and was funded and sponsored by the NIMH, It studied patients similar in inclusion and exclusion criteria to those studied in the Neuronetics trial, It used the same device as was used in the Neuronetics trial, the NeuroStar TMS Therapy System, It incorporated several additional innovations, including the use of an active sham condition to address questions of adequacy of the study blind in TMS trials, and The results were published in the Archives of General Psychiatry.   The main results of this study confirmed the observations of the earlier Neuronetics trial, and showed a statistically and clinically significant outcome on the primary efficacy measure of remission.   For those patients on sham treatment who did not improve, an open-label extension study was also offered. In that open-label extension, about 30% of patients were able to achieve remission after treatment with TMS.   This study also confirmed the safety and tolerability of TMS Therapy observed in prior studies, with a similar adverse event profile and with nearly 90% of patients fully adherent to the prescribed acute phase treatment course.   References : George, MS, Lisanby, SH, Avery, D, McDonald, WM, Durkalski, V, Pavlicova, M, Anderson, B, Nahas, Z, Bulow, P, Zarkowski, P, Holtzheimer, P, Schwartz, T, Sackeim, HA. (2010) Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: A sham-controlled randomized trial. Archives of General Psychiatry 67(5) :507-516
  22. The published scientific evidence supporting the antidepressant effect of TMS is substantial, and now spans nearly twenty years of scientific research, involving more than 30 published studies, and over 2000 patients.   There are twelve published meta-analyses or qualitative reviews of this research. The most recent and comprehensive of these was reported by Slotema and colleagues last year. They analyzed the results of 34 studies involving 1,383 patients. They computed an effect size of 0.55 (P &lt; 0.001), which represents a moderate to large clinical effect of TMS in the treatment of depression.   In their conclusion, they noted that “…rTMS deserves a place in the standard toolbox of psychiatric treatment methods, as it is effective for depression…and has a mild side effect profile…”.   References: Slotema, CW, Blom, JD, Hoek, HW, Sommer, IEC. (2010) Should we expand the toolbox of psychiatric treatment methods to include repetitive transcranial magnetic stimulation (rTMS)? A Meta-analysis of the efficacy of rTMS in psychiatric disorders. Journal of Clinical Psychiatry 71(7) :873-84. Schutter, DJLG. (2009) Antidepressant Efficacy of High-Frequency Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex in Double-Blind Sham-Controlled Designs: A Meta-Analysis. Psychol Medicine , 39 :65-75.
  23. An overall summary of the main safety findings are shown on this slide:   As I discussed earlier in reviewing its mechanism of action, TMS showed no systemic side effects, There were no adverse effects on cognition as measured by formal cognitive testing using the Mini Mental Status Examination (a measure of global cognitive function), the Buschke Selective Reminding Test (a measure of short-term memory), and the Autobiographical Memory Interview Short Form (a measure of long-term memory), The most commonly reported device-related adverse event was scalp pain or discomfort in about a third of all patients, Only about 5% of patients discontinued due to adverse events, and for the majority of patients, the device-related adverse events subsided substantially after the first week of treatment Long term safety was confirmed in a six month period of follow up after benefit from acute treatment   Seizure is the major, medically significant potential safety risk of TMS. During clinical trials, no seizures were observed with the NeuroStar TMS system. In post-market use, the risk of seizure is rare. Since market introduction and based on current usage, an estimated risk of seizure is approximately 0.003% per treatment exposure, and &lt;0.1% per acute treatment course. To date, over 150,000 treatments and more than 5,000 patients have been treated with the NeuroStar TMS Therapy system which confirms its safe use in the treatment of depression.   References : Janicak, PG, O’Reardon, JP, Sampson, SM, Husain, MM, Lisanby, SH, Rado, JT, Demitrack, MA. (2008) Transcranial Magnetic Stimulation (TMS) in the Treatment of Major Depression: A Comprehensive Summary of Safety Experience from Acute and Extended Exposure and During Reintroduction Treatment. J Clin Psychiatry 69(2) :222-232. Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199.
  24. This slide shows another important safety observation. The risk of emergent suicidal ideation is a concern with any antidepressant treatment.   In the analysis shown on this slide, Item 3 of the Hamilton Depression Rating Scale (the Suicidal Ideation item), which ranges from 0 to 4, was used. The slide depicts the proportion of patients in either the active TMS or sham TMS treatment group in the randomized controlled trial who came in with no suicidal ideation (an Item 3 score of 0 or 1) at baseline, and who later experienced an abrupt emergence of suicidal ideation (a score of 3 or 4) at any later time point.   It can be seen that virtually all of these instances occurred only in the sham treatment condition. This indicates that TMS is not associated with provoking emergent suicidal ideation during acute treatment in the indicated patient population.   References : Neuronetics, Inc., data on file. Janicak, PG, O’Reardon, JP, Sampson, SM, Husain, MM, Lisanby, SH, Rado, JT, Demitrack, MA. (2008) Transcranial Magnetic Stimulation (TMS) in the Treatment of Major Depression: A Comprehensive Summary of Safety Experience from Acute and Extended Exposure and During Reintroduction Treatment. J Clin Psychiatry 69(2) :222-232.
  25. TMS employs the same type of pulsed magnetic field technology used in modern MR imaging equipment. While the safety of this medical technology in short and long term exposure is well established, Neuronetics also characterized the long-term safety outcomes of patients treated with TMS during six months of follow up after cessation of acute treatment.   The design of this open-label follow up study is shown in this diagram. Following completion of acute treatment with TMS alone, all patients were transitioned during a 3 week Taper Phase off of TMS and onto single antidepressant medication maintenance.   The choice of medication was based on clinician and patient preference, but could not include use of a medication to which the patient had previously been non-responsive. The most commonly used medications in this study in long-term follow up were duloxetine and bupropion.   During the 6 months of follow up, patients were not permitted to modify or add to the single medication regimen in any way. TMS treatment was permitted if the patient experienced symptom recurrence, as measured by the protocol rating scales.   References : Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199.
  26. The major results of this long-term, open-label safety follow up are shown here.   No new safety observations related to TMS were reported.   Approximately 37% of patients experienced symptom recurrence requiring reintroduction of TMS. For those patients, about 85% benefited from reintroduction of TMS given in addition to their ongoing antidepressant medication.   Over 6 months of follow up, the net incidence of illness relapse (ie, those patients who deteriorated without receiving TMS and exited the study, or those patients for whom TMS reintroduction was not effective) was about 11%. This compares favorably to the long-term relapse reported in open-label naturalistic follow up in the STAR*D study, where 6 month relapse rates in Level 2 or 3 patients ranged as high as 35-50% despite continued best efforts at treatment as usual.   References : Janicak, PG, Nahas, Z, Lisanby, SH, Sovason, HB, Sampson, SM, McDonald, WM, Marangell, LB, Rosenquist, PB, McCall, WV, Kimball, J, O’Reardon, J, Loo, C, Husain, MH, Krystal, A, Gilmer, W, Dowd, SM, Demitrack, MA, Schatzberg, AF: (2010) Long-Term Durability of Acute Response to Transcranial Magnetic Stimulation (TMS) in the Treatment of Pharmacoresistant Major Depression. Brain Stimulation 3 :187-199. Rush, A. J., M. H. Trivedi, et al. (2006). &quot;Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report.&quot; Am J Psychiatry 163 (11): 1905-1917.