Attention-Deficit/Hyperactivity Disorder

John D. McLennan, MD, PhD, FRCPC Child Psychiatry Consultant

University of CalgaryPediatric Resident Seminar

Jan 17, 2013

I have no conflict of interest to declare ◦ None to declare

Common Significant Impact

◦ Risk for scholastic problems academic underachievement, grade retention, drop out

◦ Risk for relationship/social problems ◦ Risk for employment problems ◦ Risk for physical health problems

E.g., motor vehicle accidents

A. Diagnostic aspectsB. Intervention aspects C. Other

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1. ADHD as a categorical disorder

2. ADHD as a dimensional phenomenon

3. Prevalence/etiology/prognosis4. ADHD and comorbidity5. Recommended diagnostic

approach

Details Example

A (1). Six (or more) of the following symptoms of inattention have persisted for at least six months to a degree that is maladaptive and inconsistent with developmental level:

Often fails to give close attention to details or makes careless mistakes in schoolwork, work, or other activities

Often has difficulty sustaining attention in tasks or play activities

(a total of 9 symptoms listed)

(2). Six (or more) of the following symptoms of hyperactivity-impulsivity ….

Often fidgets with hands or feet or squirms in seat

Often blurts out answers before questions have been completed

(a total of 9 symptoms listed)

B Some (of these) symptoms have caused impairment were present before age 7 years

C Some impairment present in at least 2 settings

D Clear evidence of significant impairment

E Not occurring exclusively during certain other disorders

Combined Predominately, hyperactive-impulsive

◦ Likely just a precursor of combined type or just milder form

Predominately, inattentive◦ Some previously combined type◦ Some sub-threshold combined type◦ Some sluggish cognitive tempo?

Not-otherwise-specified (NOS)

◦ Forgetful, daydreams, sluggish, drowsy◦ Hypoactive◦ “in a fog”◦ Slow to process information/ more errors with

information processing ◦ Socially passive, withdrawn◦ McBurnett et al., 2001

Change Issue

Change age of onset

Change age of onset from 7 to 12 and just require symptoms (not impairment) at age of onset

Change in subtypes

-Change subtype to a specifier for presentation (as more variation in degree rather than kind, lack of stability over time)-add 4th option (“inattentive presentation-restrictive”)

Change/expand symptom examples

-to better capture lifespan relevance

Remove PDD from exclusion criteria

Many children with PDD (pervasive developmental disorder) or Autism Spectrum Disorder have significant ADHD symptom clusters

Explicitly recommend multiple informants

Pre-amble now includes recommendation to obtain information from 2 different informants

SEE www.dsm5.org for more details (..release date May 2013?)

o While ADHD is often conceptualized or promoted as a categorical entity, it probably better fits on a spectrum

Consider degrees of attentional weakness and poor impulse control

Setting a diagnostic cut-point on a spectrum Hypertension analogy

(≥140/90, not 139/89)Attention regulation

Far below average

Below average

Slightly below average

Average

Slightly above average

Above average

Far above average

Give close attention to detail and avoid careless mistakes

Sustain attention on tasks or play activities

Listen when spoken to directly

Strengths and Weaknesses of ADHD-symptoms and Normal-behaviour (SWAN rating scale) (www.adhd.net)

• Support provided by a study of the heritability of attention problems in a Norwegian twin study (Gjone et al , 1996)

• No change in relative genetic influence across severity• Lacking evidence of a taxon (Coghill & Sonuga-Barke, 2012)

The dimensional nature of ADHD and indistinct boundaries with a normal range of behaviours may result in the notion of it being a socially constructed disorder……..although this is true of well-established medical disorders as well

DSM-IV criteria◦ Estimated about 5% prevalence (Polanczky et al., 2007)

◦ Higher in clinical samples ◦ Boys>girls (more pronounced in clinical samples)◦ Inattentive type>combined type?

Family aggregation studies ◦ If parent has ADHD, risk to offspring about 57%◦ Risk to sibling approximately 32%

Twin Studies ◦ Average heritability: 80%◦ Shared environment contribution: 0-13%◦ Non-shared environment: 9-20%

Also support from adoption research Molecular genetic research

◦ DRD4 (gene for dopamine 4 receptor) – 7 repeat version?◦ 13p16 region of chromosome 16?

(Barkley, 2006)

Some studies identified smaller brain regions: total brain volume, prefrontal volume, caudate nucleus, cerebellum-vermis (Barkley, 2006; Steinhausen 2009)

Evidence of dysfunction of the frontostriatal networks and possible other networks/regions (Cherkasova & Hechtman 2009)

Developmental lag in cortical grey matter thickening/maturation in childhood (Shaw et al., 2007)

Decreased cortical thinning in adolescents (Shaw et al., 2011)

Others (Barkely 2006)◦ Deficits on neuropsychological testing (e.g., executive functioning) ◦ Quantitative EEG – increased slow wave in frontal lobe & decreased beta

activity◦ Decreased blood flow to prefrontal regions◦ Low birth weight, white matter abnormalities, brain injuries (though

likely only small subgroup)

Environmental Toxins? ◦ Lead, alcohol, nicotine (Linnet et al., 2003)

Psychosocial Factors?◦ Not etiologic, parenting behaviour may contribute to

maintenance/worsening of oppositional behaviours Other?

◦ Sugar (no)◦ Additives (maybe): Artificial food colours (Schab & Trinh,

2004) ◦ Medication (Phenobarbital)◦ Streptococcal infection

(Barkley 2006)

Increasingly recognized as a chronic disorder Estimate that 50-70% of childhood ADHD persists

into adolescence cases (could be higher depending on criteria/measurement)

Significant heterogeneity Substantial co-morbidity influences prognosis and

course

Comorbidity: the presence of one or more disorders

It is often ADHD “AND” ____ rather than ADHD “OR” _____

Common types of co-morbidities: Oppositional Defiant Disorder [or symptom cluster of] Learning Disorder [or symptom cluster of] Conduct Disorder [or symptom cluster of] Anxiety Disorder [or symptom cluster of] Depressive Disorders [or symptom cluster of] Tic Disorders [or symptom cluster of]

ADHD Alone

ADHD +

symptoms of another disorder

ADHD +

Other disorder

Other disorder +

some symptoms of

ADHD

Dr. Gabrielle Carlson, Stony Brook University Medical Centre

Kadesjö & GiIlberg, 2001 (Swedish population study)

Diagnosis ADHD(n=15)

Subthreshold ADHD(n=42)

No ADHD(N=352)

Oppositional Defiant Disorder 60% 12% 1%

Developmental Coordination Disorder

47% 47% 9%

Reading/writing Disorder 40% 29% 7%

Tic Disorders 33% 12% 2%

At least 1 comorbid diagnosis 87% 71% 17%

At least 2 comorbid diagnoses 67% 36% 3%

Common in children with ADHD

May be (Wehneier et al, 2010): Inherent in the disorder Associated with comorbidity Secondary/consequence of ADHD

Emotional impulsiveness (Barkley 2010)

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1) You must get teacher data2) Use standardized checklists3) Consider patterns on the checklists4) Child’s behaviour in the office 5) Remember comorbidities

To make an ADHD diagnosis, you must have school data Relying exclusively on parent report about school-

behaviour is inadequate◦ Parents don’t have systematic data from school◦ Parent-teacher agreement is moderate to low

If a child is not manifesting ADHD behaviour in the classroom, they don’t have ADHD

Teachers…◦ typically have access to a normative sample to inform their

ratings◦ Have a relatively “standardized” setting◦ At least some experience with typical development◦ Often substantial observation periods to draw from

A best practice recommendation Provides systematic coverage of ADHD

items (and symptoms of comorbidities) Greater reliability than clinical interview,

but not a substitute for a clinical interview Parent AND TEACHER

Narrow/focussed (e.g., primarily measure ADHD symptoms)◦ MTA-SNAP-IV◦ ACTors◦ “Short” Connors

Broad-band (could help cover potential comorbidities) ◦ Child Behavioral Checklist (CBCL)[Achenbachs]◦ Behavior Assessment System for Children (BASC)

Informant types◦ Parent/Caregiver◦ Teacher◦ Child

Disagreement between informants common

Don’t use behaviour in the office as a proxy for behaviour at school or home

Beware of “false negatives”◦ Novel stimulating environment

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What are the evidence-based interventions for ADHD? Only 2 interventions with rigorous evidence of effectiveness

for ADHD◦ Certain behavioural modification techniques◦ Certain medication

Many other interventions out there:◦ some with a little evidence◦ some with no evidence

Methylphenidate – based products Immediate release (Ritalin, generic) Extended release

CR (Biphentin) OROS (Concerta; generic?) SR (Ritalin SR)

Amphetamine – based products Immediate release dextroamphetamine (Dexedrine, generic) Sustained release dextroamphetamine (Dexedrine Spansules) Extended release - mixed salts of amphetamine (Adderall XR)

dextroamphetamine sulfate dextroamphetamine saccharate amphetamine aspartate monohydrate amphetamine sulfate

Lisdexamfetamine (Vyvanse) Lysine + dextroamphetamine (pro-drug)

A CNS stimulant Mechanism(?): increase intra-synaptic

concentration of dopamine and noradrenaline in frontal cortex and subcortical brain regions associated with motivation and reward (Volkow et al., 2004, in NICE guidelines)

Blocks presynaptic membrane dopamine transporter (DAT) inhibits reuptake of dopamine and noradrenaline into presynaptic neurons

More potent than MPH In addition to blocking reuptake of

dopamine and noradrenaline via the dopamine transporter (DAT) it also releases dopamine and noradrenaline into the extraneuronal space by blocking intraneuronal vesicular monamine transporter (VMAT)

◦ Atomoxetine (Strattera, generic) Selective norepinephrine reuptake inhibitor Approved in Canada for ADHD

◦ Others (available but not approved for ADHD) Bupropion (Wellbutrin SR and XL, Zyban, generics) Nortriptyline (Aventyl, generics) Imipramine (Tofranil, generics) Clonidine (Catapres, Dixarit, generics) Guanfacine (Tenex) [special order only]

Guanfacine extended release [Intuniv] under review in Canada◦ Desipramine and Pemoline are no longer used

What would you start with? What would inform your decision?

scienceprogress.org

Texas Algorithm Project (Pliszka et al., 2006)

◦ 1st choice – stimulant Methylphenidate or amphetamine

◦ 2nd choice – stimulant from other class Methylphenidate or amphetamine

◦ 3rd choice atomoxetine Are there exceptions where you would chose

atomoxetine earlier? ◦ 4th choice – other monotherapy

◦ What period of time to cover? School only vs. beyond school

◦ Can the child swallow? Have to be able to swallow for methylphendiate

OROS (Concerta) and atomoxetine (Strattera) ◦ Are non-generics affordable?◦ History of medication use/response (including

family)◦ Genetic testing – not yet

What do they do? Increase attention span Decrease hyperactivity Decrease impulsivity Sometimes…

Reduce aggression Improve socialization Some measures of school performance (short-term) Reduce emotional dysregulation Improve compliance

Gastrointestinal/Appetite/Growth Decrease appetite (ensure balanced diet, calorie

supplementation) Weight loss (as above; monitor) Upset stomach (take with food) Decrease stature (mean of 1.2cm at 14 months in MTA study)

Cardiovascular Increased pulse (monitor, not typically a problem) Increased blood pressure (monitor, not typically a problem) Sudden (Cardiac) Death – not evidence of increased risk but

Screen for family history of sudden cardiac death Screen for factors increasing risk for unexpected cardiac

death Baseline physical/cardiovascular exam

ECG not required if normal exam and history ….but… …could miss Long QT syndrome and WPW

◦ EMOTIONAL◦ Increased proneness to tears ◦ Agitation/irritability◦ Too quiet/glassy eyed/“zombie” appearance,

flat/depressed (dose too high) ◦ Tics (obtain family history, monitor, possibly discontinue,

controversy) ◦ Other

◦ Headaches◦ Insomnia (may be an issue with late dosing or longer-

acting formulations)◦ Generally unfounded societal worries

◦ Personality change ◦ Entry to drug abuse & addiction

◦ Selective norepinephrine reuptake inhibitor◦ Primarily metabolized in the liver via cytochrome

P450 2D6 (CYP2D6 pathway) ◦ Slower titration than the stimulants (as may be

lag in the attainment of maximum response to a given dose)

◦ Dose/body weight recommendations “Maximum” of 1.4mg/kg/day (or 100mg, whichever

is less) Start dose recommendation 0.5mg/kg/day Typically once per day dosing (but can spilt dose: am

and late afternoon/early evening)

Rare/black box warnings: liver involvement , suicidality

Common Adverse Effect

Number Needed to Harm (NNH)*

Appetite decrease

9

Somnolence 19

Abdominal Pain 22

Vomiting 30

Dyspepsia 49

Dizziness 53

Nausea 55*-Cheng et al 2007 Psychopharmacology 194: 197-209

◦ Systematic titration schedule See Texas Algorithm approach (Pliszka et al) Why?

Substantial variation in optimal response between individuals

Assist in determination of optimal dose Avoid under and over dosing

In contrast to treatment as usual which may entail: “Typical”: try 1-2 dose and adjust over-time as

prompted by parent (or teacher) This is inadequate and will not likely lead to optimal

medication choice or dose selection

….parent reports of amount of change over time cannot serve as a substitute for an assessment of the amount of change that occurs in the classroom” (Lavigne et al., 2012 p. 341)

“Although it may be difficult and time-consuming, gathering teacher reports appears to be critical for the optimal treatment of ADHD” (Lavigne et al., 2012 p. 341)

Time point Scale correlation (% variance)

Pre-treatment 0.199 (3.96)

4 months 0.331 (11.0)

12 months 0.405 (16.4)

Parent-teacher correlations on ADHD symptoms in a primary care treatment study (Lavigne et al., 2012)

0

0.5

1

1.5

2

2.5

3

Pre-med

Pre-med

Lowdose

Moddose

Highdose

ADHD symptom severity rating (teacher)

ADHD symptomseverity

NORMATIVE

SEVERE

0

0.5

1

1.5

2

2.5

3

Pre-med Pre-med Low dose Moddose

ADHD symptom severity rating (teacher)

ADHD symptomseverity

"Too quiet, seems flat, lost his spark"

SEVERE

NORMATIVE

0

0.5

1

1.5

2

2.5

3

Pre-med

Pre-med

Lowdose

Moddose

Moddose

ADHD symptom severity rating (teacher)

ADHD symptomseverity

SEVERE

NORMATIVE

0

0.5

1

1.5

2

2.5

3

Pre-med Pre-med Low dose Moddose

High dose

ADHD symptom severity rating (teacher)

ADHD symptomseverity

SEVERE

NORMATIVE

◦Maintenance/Long-term treatment Chronic disorder Less developed protocols for chronic treatment Typical recommendation

At least a brief trial off once a year to reassess benefits Dose adjustment may be required over time Long-term maintenance likely low Monitor height and weight

Long-term risks Maybe stature

Long-term benefits May reduced drug abuse (or not) Academic benefits not clear

Medication Questions?

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Behavioural parent training◦ “Well-established”

School-based behavioural interventions◦ “Well-established”

(Pelham et al., 1998; Chronis et al, 2006)

Parenting practice as a focus of treatment though not etiologic, poor practices may worsen course, improved

practices may improve function Typical components in evidence-based interventions

Review video-taped models Practice through role-playing Homework assignments Explicit multi-step curriculums

Individual explicit curriculum E.g., Barkley Parent Training Program

Group-based E.g., Incredible Years (Webster-Stratton)

◦ Teach positive reinforcement skills ◦ Positive attending and ignoring skills during “special

time” ◦ Attending positively to appropriate independent play

and compliance with simple requests◦ Use of reward oriented home token/point system◦ Response cost for non-compliance and rule violations◦ Time-out from reinforcement

◦ Interventions are easier said than done◦ Doesn’t mean parenting caused ADHD◦ Not all parent training programs are

evidence-based or effective Should have specific curriculum, with specific

skill development using evidence-based strategies, modeling, homework, etc. (organized with multiple sessions)

Different than a parent support group◦ Not adequate for improving school behaviour◦ Uptake & completion can be poor

Antecedent-based strategies

Consequent-based strategies

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Antecedents: environmental events that precede (and may trigger) specific behaviour

Examples of antecedent strategies◦ Post and strategically review classroom rules

Pair with more frequent praises when rules followed◦ Reduce task demand by reducing length or

content of assignment◦ Giving task choice for assignment

However still aimed at developing skill

• Consequences: manipulation of environmental events following a specific behavior (to alter frequency of that behaviour)

• Examples of consequence-based strategies• Response Cost

• E.g., token reinforcers are removed contingent on disruptive, off-task behaviour

• Contingent positive reinforcement• Praise• Token economy• Daily Behavioural Report Card

AKA “home-school notes” A mechanism to document behaviour, give

feedback, and intervene Some key components of DBRC

◦ Specification of clear target behaviour(s)◦ Periodic judgment about behaviour on simple scale◦ System of daily monitoring◦ Communication component between teacher and

home May be delivered as a one piece of

multicomponent interventions Effectiveness indicated in recent meta-analysis

(Vannest et al, 2010)

Relying on written recommendations or a single consultation session likely inadequate

Lack of understanding of underlying behavioural principles◦ E.g., reinforcement of escape behaviour

Premature discontinuation of attempt Lack of adjustment in targets/rewards over time Lack of tracking progress over time

The Good Behavioural Card Program (GBCP)

A collaborative effort within the COPE program

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Modeled on the Daily Behavioural Report Card from the University of Buffalo

Provide an initial 4 consultation sessions with teacher and parent of identified student◦ Introduction packets given to parents and teachers

Outline of program, examples given, request homework to generate initial ideas (targets and rewards

◦ 1st session: Develop clear target goals, and reward structure, schedule

follow-up◦ 2nd -4th session

review progress, modify target goals & rewards as needed, troubleshoot

◦ Extend if needed and progress anticipated

Daily Good Behaviour Card

# 2

Child’s name:

Date:

Target Goals Period 1 Period 2 Period 3

1 Quietly Raising Hand

2 Starting Assignment

3 Keep on Working

A home reward is earned if [child] gets at least 5

__________________Parent’s signature Parent to check box if a home reward received

Today, [child] earned ____

________________Teacher’s signature

Goal 1: (modified) Quietly Raising Hand: Hand: [Child] will raise his hand and not blurt out during group activities. This will be monitored on three occasions per day. If [chidl] can accomplish this task with less than 2 warnings/reminders he will receive 1 smiley point. This will be repeated on three separate occasions each day. The teacher will provide [child] feedback after each occasion and provide the smiley face if successful. (The modification is to drop from less than 3 to less than 2 warnings).

Goal 2: Starting Assignment: [child] will produce at least one sentence for writing projects on three occasions per day. If [child] can accomplish this task with less than 3 warnings/reminders then he will receive 1 smiley point for each of the three occasions. The teacher will provide [child] feedback after each occasion and provide the smiley face if successful.

Goal #3 : Keep on Working: If the teacher “catches” [child] persisting or finishing a writing task (after above initiation), she will give him a point (smiley face). The teacher can provide one reminder if he is not demonstrating the behavior when she does her first follow-up check on him. There will be 3 different occasions during the day (lining up with the same periods as for Goal #2). He can earn a smiley face for each of these, i.e., up to 3 points/day.

Total for the dayIf [child] gets at least 5 out of 9 total for the day he is eligible for a home reward.

(Also, [child] is eligible for an in-school reward after every 3 smiley faces he receives in a given day – 5 minute computer time)

Today’s date Summary of success with Goal #1Note down total number of smiley faces per day on this goal (out of total of 3)

Summary of success with Goal #2Note down total number of smiley faces per day on this goal (out of total of 3)

Summary of success with Goal #2Note down total number of smiley faces per day on this goal (out of total of 3)

Total for the dayNote down total number of smiley faces for the day (Goal 1 + Goal 2 + Goal 3)(Total possible: 9)

◦ Meds + Beh Mixed results as to whether combination superior to

medication MTA study

Combination treatment was not superior to medication alone overall However, medication doses lower in group receiving

the combination treatment Some sub-groups (co-morbid disorders) may do better with

combination treatment May depend on outcome measure Apparent biases against behavioural component in design,

measurement and reporting (Pelham, 1999) Maybe a serial approach

1. Behavioural modification first◦ Add medication for residual if necessary

◦ Possibly at lower doses 2. Medication first

◦ Add behavioural modification for residual if necessary

3. Simultaneous use◦ may not be needed; expensive; difficult

evaluating dosing/components

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◦ Changing the classroom environment Moving student’s desk away from others/closer to teacher Closed classrooms Structure/routine Visual aids

◦ Task & instructional modifications Reduce task length Divide tasks into subunits Goal setting Shorter time intervals Increased stimulation on tasks

◦ Computer-assisted instruction Highlight essential material Multiple sensory modalities Dividing content material into smaller chunks Provide immediate feedback Game-like format

Academic Interventions

Focusing on Success Teaching Children with ADHDhttp://www.education.alberta.ca/admin/supportingstudent/diverselearning/adhd.aspx

Consider extent of evidence Most marketed A/C strategies have little to no

scientific evidence Possible exception, omega 3 fatty acids

◦ E.g., RCT of eicosapentanenoic acid (EPA) Gustafsson 2010 While not total overall ADHD score improvement, teacher inattention

ratings significantly better & subgroup with ODD better vs. placebo

◦ E.g., Omega-3 Fatty Acid, meta-analysis Bloch & Qawasmi, 2011 10 trials with 699 children Small but significant effect for ADHD symptoms

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AAP 2011 guidelines◦ http://pediatrics.aappublications.org/content/early/2011/10/14/peds.2011-2654◦ Make sure to look at the supplement

CHADD◦ Children and Adults with ADHD◦ US: www.chadd.org◦ Canada: www.chaddcanada.org

CADDRA◦ The Canadian Attention Deficit Hyperactivity Disorder Resource Alliance◦ http://www.caddra.ca

Subcommittee on ADHD (2011) ADHD: Clinical practice guidelines for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics http://pediatrics.aappublications.org/content/early/2011/10/14/peds.2011-2654

American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders IV

American Psychiatric Association (2010) DSM-5: Options Being Considered for ADHD. www.dsm5.org

Block M & Qawasmi (Sept 2011, in press) Omega-3 fatty acid supplementation for the treatment of children with attention-deficit/hyperactivity disorder symptomatology: systematic review and meta-analysis. JAACAP

Cherkasova M, Hechtman L (2009) Neuroimaging in attention-deficit/hyperactivity disorder: beyond the frontostriatal circuitry. Can J of Psychiatry 54(10): 651-664.

Chronis A et al (2006) Evidence-based psychosocial treatments for children and adolescents with attention-deficit/hyperactivity disorder. Clinical Psychology Review 26: 486-502.

Coghill D, Sonuga-Barke E (2012) Annual research review: Categories versus dimensions in the classification and conceptualisations of child and adolescent mental disorders – implications of recent empirical study. Journal of Child Psychology & Psychiatry 53(5): 469-489.

Epstein J et al (2008) Community-wide intervention to improve the attention-deficit/hyperactivity disorder assessment and treatment practices of community physicians. Pediatrics 122: 19-27

Gustafsson P et al (2010) EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD. Acta Paediatrica 99: 1540-9.

Lavigne J et al (2012) Can parent reports serve as a proxy for teacher ratings in medication management of ADHD? Journal of Developmental & Behavioural Pediatrics 33:336-342

Leslie L et al (2004) Implementing the American Academy of Pediatrics Attention-Deficit/Hyperactivity Disorder Diagnostic Guidelines in Primary Care Settings. Pediatrics 114 (1): 129-140.

MTA Cooperative Group (1999). A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Archives of General Psychiatry 56: 1073-86.

McBurnett K et al (2001) Symptom properties as a function of ADHD type: An argument for continued study of sluggish cognitive tempo. Journal of Abnormal Child Psychology 29(3): 207-213.

Pelham W et al (1998) Empirically supported psychosocial treatment for attention deficit hyperactivity disorder Journal of Clinical Child Psychology 27:190-205.

Pelham, W. E. (1999). The NIMH multimodal treatment study for attention-deficit hyperactivity disorder: just say yes to drugs alone? Canadian journal of psychiatry, 44(10), 981–990.

Pliszka et al. (2006) The Texas Children’s Medication Algorithm Project: Revision of the Algorithm for Pharmacotherapy of Attention-deficit/Hyperactivity Disorder. Texas algorithm project 45(6): 642-657.

Pliszka et al (2007) Practice parameters for the assessment and treatment of children, adolescents, and adults with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry 46:894-921

Polanczyk MD, de Lima MD, Horta MD, Biederman MD, Rohde MD. The Worldwide Prevalence of ADHD: A Systematic Review and Metaregression Analysis. Am J Psychiatry. 2007 Jun 1;164(6):942–8.

Schab D, Trinh N (2004) Do articifical food colors promote hyperactivity in children with hyperactive symdromes? A meta-analysis of double blind placebo controlled trials. Devp & Beh Pediatrics 25(6): 423-434

Shaw P et al (2007) Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proceedings of the National Academy of Science of the USA 104 (49): 19649-54.

Shaw P et al (2011) Cortical development in typically developing children with symptoms of hyperactivity and impulsivity: support for a dimensional view of attention deficit hyperactivity disorder. American Journal of Psychiatry 168(2): 143-51.

Steinhausen H (2009) the heterogeneity of causes and courses of attention-deficit/hyperactivity disorder. Acta Psychiatra Scand 120:392-399.

Zolotor A, Mayer J, Hill J (2004) Does a short symptom checklist accurately diagnose ADHD? J Fam Pract. 53(5):412-6