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Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus of Psychiatry Ohio State University

Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

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Page 1: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Attention Deficit, Impulsiveness, and Hyperactivity:

Trait & State, Causes & Context;Conclusions to Dye for

L. Eugene Arnold, M.D., M.Ed.Professor Emeritus of Psychiatry

Ohio State University

Page 2: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Disclaimers• Have not done original research on behavioral

effect of food dyes – Just an Educated Consumer

• But much research on ADHD Tx• Selected by FDA to represent CHADD–Awkward position–Consulted with CHADD, but not common

detailed position• No financial interest either direction

Page 3: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Implementation of “In Dubitas, Libertas”

• Charge is to present “ADHD 101” complementing Andrea Chronis-Toscano’s presentation

• First present CHADD position, then speak for self

• Clarify relevant features of ADHD as diagnosis and general-population symptoms

• Show relevance to dyes• Finally interim conclusions awaiting further

research

Page 4: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

CHADD Statement1. There does not appear to be compelling scientific evidence

that food dyes cause ADHD.2. There may be a small subset of children with a

hypersensitivity to certain foods or food additives, that result in an increase in activity level and/or inattention.

3. These children may benefit from an elimination of these foods or food additives from their diets

4. CHADD has no stand on the inclusion of food dyes in food consumed by the general population. We do not support or oppose the use of food dyes.

5. CHADD looks to the FDA to protect the health and well being of all our children, including those with ADHD.

6. And in doing so, we encourage the FDA to make decisions that are well grounded in the available scientific evidence.

Page 5: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Some Clarifications

• ADHD is phenomenological, not causal Dx• Many causes common phenotype• However, the phenotype itself is pleomorphic:–Predominantly inattentive type–Predominantly hyperactive-impulsive–Combined type–Not otherwise specified

Page 6: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Diagnostic Procedure• Diagnosis requires 5 criteria:

1. Symptom count and severity2. Impairment3. Pervasive across settings4. Chronicity5. Not better explained by other mental

disorder• Because of first criterion, ADHD is dimensional

diagnosis, like hypertension

Page 7: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Analogy to Hypertension

• Everyone has some blood pressure (BP)• Too much is problem• How to set the threshold for problematic BP?• Wherever it is set, some people on the cusp• Stress, excess salt, obesity can nudge some

over the BP threshold• Don’t need diagnosable hypertension to be

harmed by stress, excess salt, obesity.

Page 8: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Chronicity & Pervasiveness CriteriaAffect measurement

• Consistent pattern of Behavior over time• In more than one setting.• Therefore cannot be measured or appreciated

in short time fragments in artificial setting• Must depend on caregiver ratings: P & T–Or at least caregiver informants

• Subjective, but most valid• FDA indications for ADHD drugs on basis of

caregiver info.

Page 9: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Causes of ADHD Are Multifactorial

• Genetics and Epigenetics–Up to 80% heritable (at least 50%)–Does not mean it’s only 20% environmental

• Genes expressed only by interaction with environment (including diet)

• PKU example: 100% heritable, 100% environmental/dietary

• Heritability could partly be genes for vulnerability to specific environmental factors

Page 10: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Multifactorial Hydraulic parfait for ADHD

Page 11: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

First Suspected Causes: MBD• “Reproductive casualty”– Increased fetal salvage– More hypoxia, trauma, bleeds; Kernicterus?

• Infections, parasites– Von Economo’s encephalitis– Intrauterine rubella– Measles, Streptococcal infection, etc.– New pathogens

• Head trauma, child abuse interaction

Page 12: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Increased Prevalence & Putative Causes

• ADHD 3-5% in 1970, as late as 1994 DSM; now estimated up to 10-12%

• Increased recognition, more liberal Dx• Multiple environmental changes in past century– Educational setting and demands–Parents working outside home– Social breakdown–Color TV? --lack of cerebellar exercise?–New chemicals in environment

Page 13: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Environmental Contaminants & ADHD Sx

• Lead, other heavy metals–1970s correlations, Pb in gasoline removed – Subclinical levels correlated same as dyes in

Southhampton results. ---Needleman

• Insecticides associated with ADHD Sx severity– Organophosphate insecticide residues &

metabolites in children’s urine, 2X the risk -- Bouchard et al, Pediatrics, 2009, June 2010, 125(6).

–Maternal gestational serum insecticide delayed effect on child age 5 -- National Institute of Environmental Health Sciences, 2009

Page 14: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Environmental Contaminants --2

• Industrial, construction, & consumer product chemicals–Cord blood PCB: top 25% 1.76X risk of ADHD

Sx as bottom 25% --- Sagiv SK, et al. American Journal of Epidemiology, January 27, 2010, Online Early.

–Polyfluoralkyl levels age 12-15 associated with ADHD -- Hoffman K,. Environmental Health Perspectives, June 15, 2010, Online Early. National Institute of Environmental Health Sciences

• Artificial food dyes– Evidence already presented

Page 15: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Consumption of Dye over Time

1950 1960 1970 1980 1990 2000 20100

10

20

30

40

50

60

70

Trends in Estimated Consumption of Food Dyes

Years

Dye

Amou

nts p

er d

ay p

er ca

pita

(mill

igra

ms)

Page 16: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Nutritional Issues over Time• Foods fewer minerals from 1930s to now– Intensive farming fertilizes only with big 3

• Deficiencies of Fe, Zn, Mg reported in ADHD cf. to controls

• Non-anemic Fe deficiency can result from high carb diet (fries, chips, sugar, pastry)

• Fe is cofactor for synthesizing DA and NE, implicated in ADHD

• Some may be genetically more vulnerable

Page 17: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Nutritional Issues over Time• Change of PUFA ratio from 5:1 to 50:1

omega3 : omega6 with intensively grain-fed meat animals and vegetable oils–Compete for desaturase enzymes–Omega3 deficiency impaired visual attn–Differences in PUFA profiles reported in

ADHD–Omega 3 supplementation medium effect

Page 18: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Nutritional Issues over Time• Interaction with intra-uterine stress: nicotine

exposure from gestational smoking–Association of maternal smoking prenatally

and postnatally with ADHD in child. Possible genetic link

• “Thrifty phenotype” (epigenetic)• On average, kids with ADHD taller and heavier,

with higher BMI (if not treated with a stimulant)

---MTA data

Page 19: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Food Dye Interaction with Nutrient• 10 HA vs. 10 controls: lower serum, urine, nail Zn• Tartrazine challenge: serum & saliva Zn down, urine Zn

significantly up in HA, not controls• Behavior deterioration correlated with Zn change• Replicated in 23 HA parent-reported to react to food

dye, compared to age/sex-matched controls• 50 mg dye challenge:– Again serum Zn down, urine Zn up compared to

controls• Zn changes from dye challenge were associated with

behavioral deterioration in both studies• Ward NI et al (1990), J. Nutr. Med. 1(1):51-58.• Ward NI (1997), J. Nutritional & Environmental Medicine 7(4): 333-342

Page 20: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Prevalent Flaws in Published Research on Dietary Sensitivities (Not Every Study)

• Diagnosis often not following DSM– Often just rating scale or clinical impression

• Blinding partial– Better blinding for food dyes

• Various mixes of dyes– Can’t tell how much each contributes to effect

• Sometimes also preservatives– Not same class– Different economic, PH implications

Page 21: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Mixing Study of Dyes with Other Dietary Components

• Often start with oligoantigenic “few foods” diet and openly add back components to find offenders

• Then double-blind challenge with offenders that can be blinded

• Dyes one of the easier things to blind– Tasteless, camouflaged by dark food or drink– Preservatives also easy to blind– Therefore better studied than other components,

but should not be considered the whole problem

Page 22: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Elimination Diets: Dyes Prominent But Not Solely Responsible

• 76 selected HA children• 62 improved on open oligoantigenic diet– also headaches, bellyaches, fits improved

• 28 into DB, placebo crossover• Sx returned more often with suspected food• 48 foods incriminated– colors and preservatives most often, not alone

» Egger J. et al, Lancet Mar.9, 1985, pp.540-545

Page 23: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Elimination Diets: Food Coloring

• 55 selected from 220 hyperactive children• 40 improved on “Feingold diet” (no dyes)• 26 remained improved after liberalization• Parents of 14 claimed specific HA behavior• 8 had DB Xover with 50 mg tartrazine or

camoisine• 2 reactors: irritabilility, restless, insomnia

» Rowe KS Australian Ped. J. 24(2):143-147, 1988

Page 24: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Elimination Diets: Denominator Problem & Controls’ Reaction

• 200 selected from 800 hyperactive• 150 improved openly to elimination of dye,

with deterioration on open addition of dye• 34 of these and 20 controls in Db challenge

with 6 doses tartrazine and placebo.• 19/23 “suspected reactors”, 3/11 “uncertain

reactors”, and 2/20 controls clearly reacted• Irritable, restless, sleep disturbance

» Rowe & Rowe, J. Ped. 125(:691-698, 1994

Page 25: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Southhampton StudiesPuzzling results by age: interaction with A & B• Preschool reacted to Mix A same as in first

study --constitutes replication • Mix B substituted quinoline yellow and allura

AC for tartrazine and ponceau 4R • Could tartrazine and/or ponceau 4R be

necessary for preschool reaction?• Older children reacted to Mix B, not A on ITT:–More sensitive to quinoline yellow and/or

allura AC --or higher dose?

Page 26: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Biological Basis of Dye Sensitivity • Gene polymorphisms moderated effect of dye

mixes on global hyperactivity scoreSignificant Histamine genes:• HNMT Thr105Ile both ages (Southhampton)• HNMT T939C for 8-9 year oldsSignificant Dopamine gene:• DAT1 in 8-9 year-oldsNot significant:COMT val108met, ADRA C1291G, DRD4 rs740373

Page 27: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Interaction of Dye Effect with Histamine Genotype (8-9-yr-olds) --2

Stevenson et al, AJP, 2010

Page 28: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Physiological Evidence:Brain Topographical Mapping

• BEAM with and without provoking food (preceding weeks and same day)

• Crossover with blind interpretation of EEG• With provoking food, increase in

frontotemporal Beta-1 band activity and behavioral symptoms

• Actual challenge not blinded–Parents could have influenced child’s EEG

• Uhlig T et al, Eur. J. Pediatr. 1997, 156(7):557-561

Page 29: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Other Evidence Biological Effect

• Erythrosine-induced inhibition of serotonergic activity in rats Dalal &Poddar, Pharmacology, Biochemistry, & Behavior, 2009, 92:574-582

• Corticosterone effects of erythrosine in rats Dalal &Poddar, Toxicology Mechanisms & Methods, 2010, 20:287-297

• Changes in liver function tests from mixtures in rats Aboel-Zahab et al, Boll.chim.Farmaceutico, 1997, 136:615-627

• Human mast cell degranulation w. tartrazine, histamine release Schaubschlager, 1987; Murdock, 1987

Page 30: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Conclusions Need more research:• Sample selection/characterization– Specialty clinics vs. general, normal

“controls”–Address the denominator problem

• Careful diagnosis by DSM• Unbundling:– Specific dyes as well as mixes–Dyes separate from preservatives

• Age effects: adolescents, adults?

Page 31: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Conclusions: Need more research (cont’d):

• Dose effects: how much is too much?• How much by the highest ingesting children?• Careful blinding–Double-blinding to prevent telegraphing

• Standard scales & observations• Examine interaction with nutrients• Examine interaction with medications• Examine effects on whole classroom as well as

individual children

Page 32: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Interim Working Conclusions (LEA)• Food dyes not the main cause of ADHD• But may contribute significantly to some cases–May additively push over the diagnostic

threshold• Several threads of biological mechanism• Probably not an Immune-mediated reaction• Deleterious effect not confined to ADHD

(general effect replicated)• Probably more a general public health

problem than an ADHD problem

Page 33: Attention Deficit, Impulsiveness, and Hyperactivity: Trait & State, Causes & Context; Conclusions to Dye for L. Eugene Arnold, M.D., M.Ed. Professor Emeritus

Working Conclusions – PH Issue (LEA)

• Small deleterious effect regardless of Dx was replicated and possible mechanism identified

• Magnitude of reported effect reminiscent of subclinical lead poisoning (<10 mcg/dL): d=0.17 after correction for social factors --Needelman

• Per capita consumption quadrupled last 50 yr.– “The dose alone makes the poison” --Paracelsus

• Possible effect on classroom climate from most children deteriorating slightly