Louis B. Cady, MD, FAPA, CEO & Founder – Cady Louis B. Cady, MD, FAPA, CEO & Founder – Cady Wellness Institute Wellness Institute Adjunct Clinical Lecturer – Indiana University School of Medicine Department of PsychiatryChild, Adolescent, Adult & Functional Neuropsychiatry –

Evansville, Indiana

New Concepts in the Epidemiology, Diagnosis and Precision Treatment of ADHD in Children, Adolescents, and Adults

IMMH 5th Annual ConferenceSan Antonio, TX Sunday, Sept. 21

Continuing Medical Education Commercial Disclosure Requirement

I, Louis B. Cady, M.D., have the following commercial relationships to disclose:

• Speaker faculties: Forest Pharmaceuticals, Sunovion, Shionogi, Takeda-Lundbeck

•Testing laboratories: Immunolaboratories, Great Plains Diagnostic Labs, LABRIX•Commercial endeavors: Pharmanex distributor•Historical honoraria, speaking: Bristol-Myers Squibb, Celltech, Cephalon, Eli Lilly, Glaxo Smith Kline, Janssen, McNeil, Pfizer-Roerig, Sanofi~aventis, Searle, Sepracor, Shire, Takeda, WorldLink Medical, Wyeth-Ayerst

www.slideshare.net/lcadymd

This is where to follow along on your tablets and smart

phones, or access the presentation slides later…

Prevalence: how much, and “why so much”?

Increased methylphenidate usage for attention deficit disorder in the 1990’s.

Safer DJ et al. Pediatrics. 1996 Dec; 98(6 Pt 1):1084-8}

• 2.5 X increase in MPH tx between 1990 and 1995– 2.8% (1.5 million) US youths aged 5-18 received this

medication in mid-1995

• “The increase in methylphenidate…appears largely related to– an increased duration of treatment;– More girls, adolescents and inattentive youths on the

medication– And a recent improved public image of medication

treatment.”

Prevalence data of parent report of ADHD “CURRENT Dx” by provider

http://www.cdc.gov/ncbddd/adhd/prevalence.html accessed 01 26 2014

2007 2011

IL 4.8% 7.2%

IN 9.3% 13.0%

KY 10.2% 14.8%

Rates of ADHD diagnosis increased an average of 3% per year from 1997 to 2006 (CDC Vital & Health Statistics)

ADHD Stats at 3-17 years of age.

• 5 million children (9% for this age group)– Boys 12%– Girls 5%

• Children with fair/poor health status 2½ X more likely to have dx. (8% vs 21%)

www.billfoster.com - Reviving American Manufacturing, accessed 1 27 2014www.billfoster.com - Reviving American Manufacturing, accessed 1 27 2014

http://www.scdigest.com/assets/newsViews/08-06-12-2.php accessed 01 27 2014http://www.scdigest.com/assets/newsViews/08-06-12-2.php accessed 01 27 2014

Unemployment, underemployment are contemporary problems…

Genetic tendencies in ADHD

Faraone SV et al. Biol Psychiatry 2005 June 1;57(11):1313-1323.

Graphic from CNS Spectr. 2007;12:4 (Suppl 6): 6- 7

Genetic etiologies

• Genes most commonly associated with ADHD involve dopamine.– Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-

deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1313-1323.

• PET studies show excess DAT into presynaptic neuron (15% higher than in controls)– Spencer TJ, Biederman J, Ciccone PE, et al. PET study examining

pharmacokinetics, detection and likeability, and dopamine transporter receptor occupancy of short- and long-acting oral methylphenidate. Am J Psychiatry. 2006;163(3):387-395.

Spencer TJ, et al. PET study examining pharmacokinetics, detection and likeability, and dopamine transporter

receptor occupancy of short- and long-acting oral methylphenidate. Am J Psychiatry. 2006;163(3):387-395.

Graphic from CNS Spectr. 2007;12:4 (Suppl 6): 6- 7

Seidman LJ, Valera EM, Makris N, et al. Dorsolateral prefrontal and anterior cingulate cortex volumetric abnormalities in adults with attention-deficit/hyperactivity disorder identified by magnetic resonance imaging. Biol Psychiatry. 2006;60(10):1071-1080.

Graphic from CNS Spectr. 2007;12:4 (Suppl 6): 6- 7

• Population:– 24 adults with ADHD

per DSM-IV– 18 controls

• Relative to controls:– significantly smaller

overall cortical gray matter, prefrontal and ACC volumes.

Narr KL, et al. J Am Acad Child Adolesc Psychiatry. Oct 2009; 48(10): 1014–1022.

• Population:– 22 children & teens with ADHD per DSM-IV – on no Rx– 22 controls– mean age of 11.7 years in both groups)

• Relative to controls:– Significant volume reduction in overall brain, gray matter,

& mean cortical thickness.– White matter volume significantly increased.

Narr KL, et al. J Am Acad Child Adolesc Psychiatry. Oct 2009; 48(10): 1014–1022.

“Cortical thickness reductions present a robust neuroanatomical marker for child and adolescent ADHD. Observations of widespread cortical thinning expand on earlier cross-sectional findings and provide further evidence to support that the neurobiological underpinnings of ADHD extend beyond prefrontal and subcortical circuits.”

Prevalence & diagnosis

(NYT, 12 14 2013)

What does it “look like”?

A section for kinesthetic and visual learners…

ADHD – not concentratingInferior Orbital pre-frontal cortex

Images courtesy of Daniel Amen, MD – Amen Clinics, Inc., Newport Beach, CA

ADHD - concentrating

ADHD – concentrating, on RX

ADD – inattentive, without Rx

ADD – inattentive, on Amph

Images courtesy of Daniel Amen, MD – Amen Clinics, Inc., Newport Beach, CA

Diagnostic criteria

DIAGNOSIS: FOUR FLAVORS OF ADHD

314.00 ADHD Predominantly Inattentive Type*

314.01 ADHD Predominant Hyperactive-Impulsive Type*

314.04 ADHD, Combined Type

314.9 ADHD – Not Otherwise Specified

5-6 of 9 symptoms required for 314.00 & 314.01

– Symptoms present before age 7 (now 12 in DSM-5) years

– Impairment from symptoms present in 2 or more settings

– Significant social, academic, or occupational impairment

– Exclude other mental disorders

Check off the symptoms which are unusually troublesome for your child (or YOU, if you are an adult patient) which are clearly different from what other children or adults typically experience. PLEASE USE THE BACK SIDE OF THIS FORM TO AMPLIFY ON ANY OF THE "CHECKED" SYMPTOMS WHICH YOU FEEL I SHOULD KNOW MORE ABOUT.

ADHD Diagnostic Symptom Checklist, adapted from DSM-IV, by:Louis B. Cady, M.D. - 611 Harriet Street - Suite 304 - Doctors Plaza

Evansville, IN 47710 www.drcady.com

PATIENT NAME: ___________________________ DATE: __________Medication status: ( ) pre-treatment? ( ) on Rx? ( ) OFF of Rx?

PATIENT STATUS: CHILD

ATTENTION PROBLEMSdisplays failure to give close attention to details; makes careless mistakeshas difficulty with sustained attentiondoesn't listen even when spoken to directlyhas REAL trouble following through on instructions; fails to finish tasksdifficulty organizing tasks/activitiesavoids, dislikes, or reluctant to engage in tasks requiring sustained mental effort (homework, work projects, etc.)loses things necessary for tasks/activitieseasily distracted by extraneous stimuli (sounds or sights in the environment)often forgetful in daily activities

HYPERACTIVITY, "WIGGLESOMENESS" PROBLEMS

fidgets with hands or feet, squirms in seatleaves seat in classroom in which remaining in seat was expected, or can't stay put at workruns about; climbs excessively in inappropriate situationsdifficulty playing or engaging in leisure activities quietlyoften was "on the go" as if "driven by a motor"talks excessively - a "chatterbox"

PROBLEMS BEING IMPULSIVEblurts out answers before questions are completeddifficulty waiting your turninterrupts or intrudes on others (butts into conversations)

For physician use only - RECENT CLINICAL HISTORY:

PARENTS: Please feel in your child's

CURRENT DRUG THERAPY... PLEASE LIST!

____________ _________ ________________________ _________ ________________________ _________ ________________________ _________ ________________________ _________ ________________________ _________ ________________________ _________ ____________

medication size of dose WHEN TAKEN

physician use...

DSM-5 update

• 6 symptoms before age 7

• 6 symptoms for adults

• 6 symptoms before age 12

• 5 (FIVE) symptoms for adults

“The Total Picture” diagnostic pearls [from Steven Grcevich, MD]

• Read comments on report cards!

• Ask siblings: “What’s (s)he like to live with?”

• Ask patient: “When was the last time you got invited to someone else’s house to play?”

• Ask parents: “Is (s)he involved with any activities in the community?”

Cf: www.cwiyoutube.com for 20 minute explanatory video

D iagnosis & The Four D’s of Malpractice

• D uty

• D ereliction of the duty

• D amages resulting• D irectly caused. (“proximate cause”)

Our call to be better doctors and health care providers.

PS: Chart SCRUPULOUSLY.

Allegedly:

•Improper diagnosis

•Failure to monitor use of Adderall– Prescribed increasing doses of Adderall in spite of

signs of drug abuse.

•Ultimately leading to patient’s suicide.

August 5, 2014

Don’t get it wrong. ADHD confounds:• Autism spectrum

disorder• Hearing impairments• Hypothyroidism• Iron deficiency

anemia• Lead toxicity• (OSA)

• 605 children: 19% snored, 10% had OSA.

• 13% had ADHD diagnosis

• 5-9% had behavioral problems or conduct disorder

• OSA symptoms were associated with:

– Two-fold increased risk of ADHD dx or sxs.

– 3 – 4X increased odds of behavioral problems or conduct disorder

Constantin E et al. Association between childhood sleep-disordered breathing and disruptive behavior disorders in childhood and adolescence. Behav Sleep Med. 2014 Aug 7:1-13.

MISS-Diagnosis and MISdiagnosis

• MISSing it– Not taking a good

history or using rating scales

– Not taking a family history.

– Poor documentation– Not testing

• MISdiagnosing ADHD– “all that wiggles is not ADHD.” – “all that is inattentive and can’t

concentrate is not ADHD.”– Don’t miss medical. – EXCLUDE Bipolar,

depression, anxiety d.o., “EFAD,” PTSD, sexual trauma

• (and CHART CHART CHART)

Different symptom manifestation: children through adults

Continuation of Impairment of ADHD

Hopelessness, frustration, giving upBecomesRepetitive failure

Unwanted pregnancy, STDs, etc.Becomes

Impulsivity and carelessness

ASPD, criminal involvement

BecomesODD / CD

Drug dependenceBecomesDrug experimentation

Fatal car wrecks / risk taking

BecomesMultiple injuries

Job failure or under-employment

BecomesSchool failure / under-achievement

Adulthood Childhood

Courtesy of William Dodson, MD – Denver, Colorado

Hyperactivity

—Age—

Impulsivity

Inattention

ADHD: Course of the Disorder

Earlier Initiation of Smoking with ADHD

237 6 to 17-year-old boys

0.6

0.5

0.4

0.3

0.2

0.1

0

Sm

oki

ng

pro

bab

ilit

y

0 2 4 6 8 10 12 14 16 18 20 22 24

P<0.003

ADHD n=128Control n=109

Milberger S, et al. J Am Acad Child Adolesc Psychol. 1997;36:37-44.

4 year follow-up

Biederman, et al. Biol Psychiatry. 1998;44:269-273.

Lif

etim

e ra

te o

f su

bst

ance

ab

use

in

ref

erre

d A

DH

D a

du

lts

0

10

20

30

40

50

60

Increased Lifetime Substance Abuse in Untreated Adults with ADHD

55% Control (n=268)

ADHD (n=239)

27%

P<0.001

Biederman J, et al. Pediatrics. 1999;104:e20-e25.

40

30

20

10

0

% o

f st

ud

y p

op

ula

tio

n

UnmedicatedADHD

MedicatedADHD

Control

32

12 10

P<0.001

Pharmacotherapy Significantly Reduces Substance Abuse in Adults

with ADHD

(N=56)(N=19)(N=137)

3-fold!

What happens if ADHD isn't treated?

Outcomes of kids with ADHD as adults

• Significantly worse educational, occupation, economic, and social outcomes

• More divorces• Higher rates of ongoing ADHD (22.5% vs. 5.1%)

• More antisocial personality disorder (16.3% vs. 0%)

• More SUD’s (14.1% vs. 5.1%)

• “The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence without onsets of new disorders after 20 years of age.”

Klein RG, Mannuzza S, et al. Clinical & functional outcome of childhood attention-deficit/hyperactivity disorder 33 years later. Arch Gen Psychiatry 2012 Dec;69(12):1295-303. doi: 10.1001/archgenpsychiatry.2012.271.

Horrigan J, et al. Presented at 47th Annual AACAP Meeting: October 24-29, 2000. New York, NY.

Driving behavior and results in 27 clinically referred German adults

• N=27, with initial screen– 19 studied – initial testing then either:

• 10- kept medication free• 9 – tx’ed for 6 weeks with MPH

Sobanski E, et al. Driving-related risks and impact of metylphendiate treatment on driving in adults with attention-deficit/hyperactivity disorder (ADHD). J Neural Trans. 2008; 115(2):347-56.

Driving behavior and results in 27 clinically referred German adults

• Background findings:– All ADHD subjects: drove significantly more kilometers per year– More often registered by traffic authorities– Fined more frequently– Involved in more MVA’s– Self described driving style as “more insecure and hectic” than

controls.

• A high risk group was delineated with:– 3-6 MVA’s per ADHD subject

Sobanski E, et al. Driving-related risks and impact of methylphenidate treatment on driving in adults with attention-deficit/hyperactivity disorder (ADHD). J Neural Transm.. 2008; 115(2):347-56.

Do you want to treat them?

STUDY CONCLUSIONS:

MPH tx improved information processingand sustained visual attention compared to baseline and untreated control groups.

Sobanski E, et al. Driving-related risks and impact of metylphendiate treatment on driving in adults with attention-deficit/hyperactivity disorder (ADHD). J Neural Trams. 2008; 115(2):347-56.

Psychiatric disorders (lifetime) in adults with ADHD [multiple sources, % is estimated; N.B. – this is WITHOUT TREATMENT GROWING UP]

• Substance use disorders (all) 50%• Anxiety disorders 40%

• Major depression 35%

• Learning disabilities 20%

• Bipolar disorder 10%

• Antisocial disorder 10%

105 Adult ADHD Drivers vs. 64 Controls (CC)

• ADHD’ers self reported:– More citations (esp. for SPEEDING),

crashes & license suspensions than CC

• ADHD’ers:– less attentive, made more errors on

visual reaction task– Lower scores on driving rules test.

• Driving difficulties: not related to “ODD”, depression, anxiety, or frequency of substance use.

Barkley RA, et al. J Int. Neuropsychol Soc. 2002 (5):655-762.

Adult ADHD’ers:• Lower self esteem as

adults• Lower educational

achievements• Greater use of ancillary

educational resources• Greater tobacco and

recreational drug use • A lifelong pattern of

“consistent inconsistency.” Source: David Goodman, MD – Johns Hopkins Adult ADHD

treatment center

Drug, drug... who's got the

drug?

We are not there yet.

Response to Psychostimulants

Best Response(Percent)

AMP MPH Equal response to either stimulant

Meta-analysis of Within-Subject Comparative Trials Evaluating Response to Stimulant Medications

28%28%

16%16%

41%41%

.Arnold et al. J Attention Dis. 2000;3:200.

Betting odds:Amph – 69%

MPH 57%

Benefit-Risk Ratio and Efficacyof Psychostimulants

• Very favorable benefit-risk ratio– rapid, dramatic results– low risk of long-term side effects

• Approximately 70% of patients with ADHD will show a positive response on the first trial of any one stimulant medication

• If two different stimulant medications are tried, the response rate increases to ~90%

Greenhill. Child Adolesc Psychiatr Clin North Am. 1995;4:123; Spencer et al. JAACAP. 1996;35:409;Goldman et al. JAMA. 1998;279:1100.

Amphetamines, methylphenidate, and antidepressants - important differences:Amphetamine - increases release and decreases uptake at the DOPAMINE uptake transporter (Seiden, et al., 1993)–effects release of DA from vesicles.

–also allows dopamine to be released from newly synthesized pools inside the cell.

–also activates 5-HT receptors (Sloviter, et al., 1978)

–L-amphetamine = 50/50 NERI/DRI (Stahl, 2013)Methylphenidate - effects release of DA from vesicles only – inhibits dopamine reuptake, as well.

Antidepressants: inhibit reuptake of NE and DA; do not cause release. [Atomoxetine = “NRI”]

Atomoxetine• Superior to placebo (but slightly

less effective than MPH) in large, double-blind, placebo-controlled trial-Heiligenstein, 2000

• Spencer et al. (JCAP 2001)-open study,30 patients, 75% improved >25%.

SE’s: rhinitis, headache, anorexia, dizziness, nervousness, somnolence

• Michaelson (Pediatrics, 2001) ATX>PLB, best response at 1.2 mg/kg/day

• Kratchovil (JAACAP, 2002) ATX=generic MPH, open-label study, inadequately poweredHeiligenstein et al. Presented at AACAP, October 24-29, 2000Spencer et al. J. Child Adolesc Psychopharmacol 2001: 11(3) 229-238

CH3

O NCH3

H

HCl

CH3

O NCH3

H

HCl

“Strattera* [coupled with fluoxetine or paroxetine] has been great for our admissions.”

-Dr. William Beute, MD

Pine Rest Campus Clinic

Grand Rapids, MI

April 21, 2004

[quoted with permission]

* Brand name used in this slide because this is a direct quote

“2P, or not 2P……that is interaction.”

NB: Cytochrome p450 2D6:-This is where atomoxetine is metabolized-It is inhibited by paroxetine and fluoxetine

“Alpha 2a agents”• Concept of SUSTAINED RELEASE AGENTS –

generic instant release agents not the same• Extended release guanfacine – “1,2,3 or 4 mg at

bedtime”• Extended release clonidine – “0.1 – 0.2mg (ER)

twice daily (a.m. and pm)” • Both are approved for monotherapy or for add-on

therapy.• Stimulants seem more potent; alpha-2 Rx seems

to be better for oppositional/defiant symptoms, either by themselves or in combination therapy.

“Mixed salts of amphetamines, "handedness,” and efficacy

Amphetamine mixed salts contains:–d - amphetamine sulfate (aka "Dexedrine")

–d,l - amphetamine sulfate–d,l - amphetamine saccharate–D,l – amphetamine aspartate

Dextro-amphetamine 2x as effective as l-amphetamine

–Smith & Davis, 1977; Janowsky & Davis, 1976

The Arnold studies

Randomized, double-blind, placebo controlled31 children with “MBD” (1976)Rx: 5 mg of d-AMP; 7 mg l-AMP [difference d.t. MW's]

CONCLUSIONS (replicated previous 1972 study of n=11):–Both agents found effective–Typically one agent was more effective than the other for individual children

[Arnold LE, Huestis RD, Smeltzer DJ, et al. Levoamphetamine vs dextroamphetamine in minimal brain dysfunction. Arch Gen Psychiatry 33:292-301, 1976

Arnold LE, et al. Levoamphetamine and dextroamphetamine: Differential effects on aggression and hyperkinesis in children and dogs. Am J Psychiatry 130:165-170, 1973]

Typically one agent was more effective Typically one agent was more effective than the other for individual childrenthan the other for individual children

• d-AMP "appeared non-significantly more d-AMP "appeared non-significantly more effective"effective"• slightly better for "over-anxious" childrenslightly better for "over-anxious" children

• l-isomer - 2/3 of children improvedl-isomer - 2/3 of children improved• seemed to be of more benefit to seemed to be of more benefit to

"unsocialized-aggressive" kids"unsocialized-aggressive" kids• 28% of responders preferred the l-AMP form28% of responders preferred the l-AMP form• ““decreased tendency to blunt affect and decreased tendency to blunt affect and

produce the produce the ‘‘amphetamine lookamphetamine look’’ [sic] [sic]””

Drug Delivery & Dosing adjustments

OROS MPH – the first player

GI liquid absorbed

into osmotic matrix pump

MPH pushed out the laser drilled

hole at end of tablet

Peaks & troughs…

OROS MPH – 18 mg

OROS MPH &

Delayed-Release Bead

Mixed amphetamine salts “XR” system

Immediate-Release Bead

Bead Core

Overcoating

Release-DelayingPolymer

Capsule

Overcoating

50% 50%

Drug LayerOvercoating

Drug Layer

Bead Core

Available in 5, 10, 15, 20, 25, and 30 mg dosing forms

Chemical Structure of Lis-dexamfetamineChemical Structure of Lis-dexamfetamine

Lis-dexamfetamine is a prodrug that is therapeutically inactive Lis-dexamfetamine is a prodrug that is therapeutically inactive until it is converted to active until it is converted to active dd-amphetamine in the body-amphetamine in the body

l-lysinel-lysine

H NH N22

OO

OHOH

NHNH 22

++

dd-amphetamine-amphetamine(active)(active)

H NH N22

CHCH33

Lisdexamfetamine Lisdexamfetamine (Prodrug)(Prodrug)

H NH N22

OO

NNHH

NHNH 22

CHCH 33

Site of cleavageSite of cleavage

Rate-limited

Hydrolysis

Charged polymer sustained delivery technology

12 hour sustained release LIQUID MPH Rx

Basic MPH 101• How much to Rx?!

• Old dosing charts show 0.3 – 0.7 mg/kg/dose– But only “1.5 mg/kg/day”….

• But THREE doses of 0.3 – 0.7 mg/kg/dose = 0.9 – 2.1mg/kg/day

• THEREFORE, theoretical maximum should be “2.1 mg/kg/day” (the “Biederman max”)

• But what is that really, in “Hoosier-speak”?

Cady/Desiderato Factor-Label, Down-Home, Good-Ole Boy MPH

Calculation:

2.1mg MPH 1 Kg ONE milligram

X =

Kg 2.2 lbs pound of kid

1mg / lb of kid / day

spread out over 12 hours, OR

About ½ that for amphetamines or dex-MPH

amphetamine salts, dex amph, dex-MPH = ½ the typical amount

of methylphenidate

So how much to dose?

• No correlation between plasma level and therapeutic response:– Big levels in small kids– Small levels in big kids

• All medication titrations should be made by informed, observant clinicians with good solid follow-up and examinations

• Titrations should be based on DYSFUNCTION

M.D. does not stand for “minor deity”• Start lower than you think you probably should. • Push it carefully until you get results

– a “just right” therapeutic effect– absent side effects

• Use the “Biederman max” as a rough rule of thumb to calculate the “ceiling,” NOT TO START!

• If you have to “break through the ceiling” – think carefully, document your rationale, monitor carefully for side effects, HTN, cardiac issues

• Explain both the “Goldilocks” and the “Cinderella” aspects to patients/parents

How to screw it up: a case study

• 1/28/14 – 7 year old child presents for tx• Oct 2013 – dx’ed with ADHD• RX:

– Started on 30 mg lys-dexamph from start • Zombied out for two days

– Dosage reduced to 15 mg. Worked well for 3 weeks. “I like the way my brain is working.”

– Began hearing voices in his head at night.

• Medication stopped• Voices persisted over the next 2 weeks, then d/c

At home: Two great “how to do it” books

Therapy Axioms: who needs it, when to do it

• The later a child (or adult) is diagnosed, the more complications (s)he has had, and the more conflict – the higher the likelihood of need for psychotherapy

• The converse applies.

• The higher the level of family dysfunction, the more the need for:– “parent training”– Behavioral therapies, etc.

Inventor of NASDAQ screen– Strong family hx of ADHD– Dx’ed at 48 yoa– Interviewed in Time

Square – “Don’t you feel proud?”

–“Not really – all my life, people were telling me I would never amount to anything.”

Quote & identity used by specific permission of David Goodman, MD [Dir., Adult Attention Deficit Disorder

Center of Maryland] & his patient

Integrated: how to avoid over-reliance on meds

• Holistic treatment and supplementation!– Cf: The Physician in Spite of Himself, Part II

• Smart prescribing!• School:

– Excellent working relationships with school– Good teaching

• HOME:– Diminish “electronic screens” effect– Good home discipline– Good sleep/wake schedules– Good diet– Adequate exercise

• Parent training: parenting, stress tips

What happened to those, anyway?!What happened to those, anyway?!

New Concepts in the Epidemiology, Diagnosis and Precision Treatment of ADHD in Children, Adolescents, and Adults

IMMH 5th Annual ConferenceSan Antonio, TX Sunday, Sept. 21

But what about the functional medicine aspects??

My Previous Notion of Therapeutic Options

My experience with a child with out of control ADHD - the story of Billy

• 8/1998 – 4 yo Eastern European adopted child – “ADD & behavioral problems, destructive.”– First 3 years of life in orphanage

• Fam Psych Hx:– Dad – “substance induced paranoid psychosis”– Mother – “recurrent schizophrenic

decompensations”

Billy, cont.

• Some improvement• 3/1999 – increasingly vile temper. Sad, dysphoric.

“Back to square one.”– Zoloft added.– Ritalin only lasting 1 ½ hours

• 5/1999 - 4 ½ yoa. Rehab Center testing:– Auditory comprehension = 2 y 11 mo’s– Total language = 2 y 11 mo’s

• 6/1999 – Flaxseed oil, L-tyrosine, Pediactive tabs added. In constant trouble Dad getting depressed.

Billy, cont – 1999 - 2000

• Ritalin and Adderall not working• Temper to the point of clawing at his face.

Sniffing. Now urinating in bed.• 12/1999 – started on Risperdal – 1mg in a.m. and

½ mg later in day• 2/2000 – Psych testing – IQ 78

– ADHD– Borderline intelligence– Processing problems– “r/o childhood psychosis”

Billy, late 2000• Fall 2000:

– Bit and stabbed his teacher with a pencil, kicked chair, wall, and desk, spat on floor and teacher. Obsessively lining up his cars in his room, tongue thrusting and smacking (? Tardive dyskinesia?)

• On Risperdal, Depakote, and Concerta.• 8/2001 – 2002 some better but still

unpredictable. Meltdowns. Depakote increased. Zyprexa added.

• 8/2002 – throwing things against windows. Depakote not working. Mood cycling.

Billy, 2003

• Ongoing unpredictability until Geodon started. – Less hyper– Dry in a.m.– Clearer speech and better eye contact.

• July 2003 – IgG food allergy testing ordered

Billy – IgG Food SensitvitiesJuly 2003

• 21 + IgG reactions.. Of these…..– Cheese (3+)– Cow’s milk (3+)– Goat’s milk (2+)– Brewer’s yeast (3+)– Millet (+1)– Lettuce (!) (+1)

Reviewed labs with internet savvy Mom (who did NOTHING).

June 7, 2004 – 6 years of tx; ONE YEAR AFTER IgG Testing!

• “Literally bouncing off the walls in the a.m.”• Almost knocked brother off second floor balcony• Could not tolerate < 2 g VPA• Threw stool over banister and tried to hit Mom on

way up stairs. (Missed) • Told Mom: “You’re going to die, I’m going to

make sure you’re going to die.” • Things that make him angry: not putting peanut

butter sandwich on plate “correctly.” • Waking up screaming. Making non-human,

guttural sounds.• Parents pursuing IP treatment

Radical interventions/ workup

• June 2004 – Lithium added– Made him briefly toxic but symptoms improved.– Worked on getting him inpatient tx.

• Fatty acid panel ordered.

• Told Mom to GET SERIOUS about food allergies/sensitivities

Clinical manifestations of EFAD

• Dermatitis• Increased appetite and

caloric intake in infants (adults?!)

• Failure of wound healing• Irritability• Alopecia, dry hair, dandruff• Brittle nails• Increased susceptibility

of infections

• Thirst, polydipsia, polyuria

• Liver fatty infiltration• Increased capillary

fragility• RBC fragility• Increased

Cholesterol/HDL ratio

Essential Fatty Acid findings

Value Reference range

EPA 3 (L) 20 - 80

DHA 32 (L) 70 - 150

FEB 2005

• The present study found that 53 subjects with ADHD had significantly lower concentrations of key fatty acids in the plasma polar lipids (20:4n-6, 20:5n-3, and 22:6n-3) and in red blood cell total lipids (20:4n-6 and 22:4n-6) than did the 43 control subjects

• “…but the precise reason for lower fatty acid concentrations in some children with ADHD is not clear.”

• The present study found that 53 subjects with ADHD had significantly lower concentrations of key fatty acids in the plasma polar lipids (20:4n-6, 20:5n-3, and 22:6n-3) and in red blood cell total lipids (20:4n-6 and 22:4n-6) than did the 43 control subjects

• “…but the precise reason for lower fatty acid concentrations in some children with ADHD is not clear.”

• “We argue that a change in the ratio of n-6/n-3, especially during early life, may induce developmental changes in brain connectivity, synaptogenesis, cognition and behavior that are directly related to ASD.”

• “We argue that a change in the ratio of n-6/n-3, especially during early life, may induce developmental changes in brain connectivity, synaptogenesis, cognition and behavior that are directly related to ASD.”

• Western diet: omega 3 fatty acid deficiency and increased fructose intake. • “Both promote brain insulin resistance and increase the

vulnerability to cognitive dysfunction.” • “Multiple cognitive domains are affected by metabolic

syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function.”

• Western diet: omega 3 fatty acid deficiency and increased fructose intake. • “Both promote brain insulin resistance and increase the

vulnerability to cognitive dysfunction.” • “Multiple cognitive domains are affected by metabolic

syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775234/

• In Adults with ADHD:• DECREASED DHA, AA, and DHGLA

• “We could demonstrate that a lack of polyunsaturated FAs in blood serum of subjects with ADHD persists into adulthood. Furthermore, we could show that adult ADHD symptomatology positively correlates with elevated levels of saturated stearic and monounsaturated FAs.HGLA were lower than controls.”

• In Adults with ADHD:• DECREASED DHA, AA, and DHGLA

• “We could demonstrate that a lack of polyunsaturated FAs in blood serum of subjects with ADHD persists into adulthood. Furthermore, we could show that adult ADHD symptomatology positively correlates with elevated levels of saturated stearic and monounsaturated FAs.HGLA were lower than controls.”

This summary demonstrates that a deficiency in brain PUFAs will lead to cognitive deficits, while supplementation of PUFAs can rehabilitate cognitive deficits, as manifested in attention deficit hyperactivity disorder, stress/anxiety, and aging.

This summary demonstrates that a deficiency in brain PUFAs will lead to cognitive deficits, while supplementation of PUFAs can rehabilitate cognitive deficits, as manifested in attention deficit hyperactivity disorder, stress/anxiety, and aging.

Should we use this??

Further elongation problems:

lack of nutrients

• REQUIRED for delta-6 desaturase:– Magnesium– Zinc– B vitamins

• FAD (B2)• Niacin (B3)• P-5-P (B6)

– C– insulin

“chiropractic” “psychiatric”

Extra slide of online viewing• Key principles of essential fatty acid

supplementation are:– Do not use large doses of a generic omega 6 or omega

3 fish oil and presume that you are going to get adequate amounts of EPA and DHA out the bottom of the pathways.

– The only two sources of fish oil high in PUFA’s that we get are from eating fish or taking fish oil. Period. If we don’t eat fish, we should probably be on fish oil.

– We DO have the ability to synthesize the critical PUFA’s, including EPA and DHA, from precursors, but in order to do so, we must have adequate amounts of the critical trace minerals.

NOTE: The essential elements portion of this test include:•Elemental lithium•Iron•Magnesium •Zinc•copper

NOTE: The essential elements portion of this test include:•Elemental lithium•Iron•Magnesium •Zinc•copper

IRON - Most common of all nutrient deficiencies in U.S. school-aged children

Murray & Pizzorno. Encyclopedia of Natural medicine. Rocklin, CA: Prima Publishing; 1998.

• Deficiency associated with: markedly decreased attentiveness, narrower attention span, decreased persistence, and lowered activity level – all of which respond positively to supplementation.

• Kidd. ADHD in Children: Rationale for Its Integrative Management. Alt Med Review 2000; 5(5):402-427.

• 30% improvement in Conners ADHD Rating Scale following iron supplementation [(Ferrocal), 5 mg/kg/day for 30 days] in one uncontrolled Israeli study of boys.

• Sever et al. Iron treatment in children with attention deficit hyperactivity disorder. A preliminary report. Neuropyshcobiology 1997;35:178-180.

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serumferritin

Conners

beforeafter

–significant increase in serum ferritin levels (from 25.9 +/- 9.2 to 44.6 +/- 18 ng/ml) and a significant decrease on the parents' Connors Rating Scale scores (from 17.6 +/- 4.5 to 12.7 +/- 5.4).

Zinc link --- and friends• Psychiatr Pol 1994 May-Jun;28(3):345-53

[Deficiency of certain trace elements in children with hyperactivity][Article in Polish]Kozielec T, Starobrat-Hermelin B, Kotkowiak L.

Zakladu Medycyny Rodzinnej Pomorskiej Akademii Medycznej.

• The magnesium, zinc, copper, iron and calcium level of plasma, erythrocytes, urine and hair in 50 children aged from 4 to 13 years with hyperactivity, were examined by AAS. The average concentration of all trace elements was lower compared with the control group--healthy children

from Szczecin. The highest deficit was noted in hair.

• Our results show that it is necessary to supplement trace elements in children with hyperactivity.

Magnes Res 1997 Jun;10(2):143-8 Kozielec T, Starobrat-Hermelin B.,, 1997, cont.

• 116 children with ADHD• Magnesium deficiency was found in 95

per cent of those examined:– most frequently in hair (77.6 per cent)– in red blood cells (58.6 per cent) – and in blood serum (33.6 per cent)

• CONCLUSIONS: magnesium deficiency in children with ADHD occurs more frequently than in healthy children. Analysis of the material indicated the correlation between levels of magnesium and the quotient of development to freedom from distractibility.

“Don’t think ‘either/or.’ Think ‘both/and.’”- Dan Burrus

“There are things known and there are things unknown, and in between are the doors.”- Jim Morrison

Contact information:Louis B. Cady, M.D.

www.cadywellness.com

www.tmsrelief.com

Office: 812-429-0772E-mail: lcady@cadywellness.com

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