Attention-Deficit Hyperactivity Disorder

ADHD Statistics

3-5% of all U.S. school-age children are estimated to have this disorder.

5-10% of the entire U.S. population

Males are 3 to 6 times more likely to have ADHD than are females.

At least 50% of ADHD sufferers have another diagnosable mental disorder.

Psychiatric Comorbidity

Anxiety(34%)

Non-comorbid(55%)

CD(8 – 20%)

4%

2%

7%

MD(20 to 30%)

7%23%

ADHD: Etiology

ADHD is a heterogeneous behavioral disorder with multiple possible etiologies

ADHD

NeuroanatomicNeuroanatomicNeurochemicalNeurochemical

CNS CNS insultsinsults

Genetic Genetic originsorigins

Environmental Environmental factorsfactors

“It’s a guy thing.”

ADHD: Adult Common Comorbid Diagnosis

FemaleMale

Risk Factors for ADHD

GirlsBoys

History of ADHDMid-1800s: Minimal Brain Damage

Mid 1900s: Minimal Brain Dysfunction

1960s: Hyperkinesia

1980: Attention-Deficit DisorderWith or Without Hyperactivity

1987: Attention Deficit Hyperactivity Disorder

1994-present: ADHD

Primarily Inattentive

Primarily Hyperactive

Combined Type

What is ADHD?

“The unifying abstraction that currently best encompasses the faculties principally affected in ADHD has been termed executive function (EF), which is an evolving concept…there is now impressive empirical support for its importance in ADHD”

– Castellanos FX. (1999) The psychobiology of attention-deficit/hyperactivity disorder. In HC Quay, AE Hogan (Eds), Handbook of Disruptive Behavior (pp. 179-198). Kluwer Academic

Executive Functions

Wide range of central control processes of the brain

Connect, prioritize and integrate cognitive functions – moment by moment

Like a conductor of a symphony orchestra

“Focus” and Executive Functioning

Intention symptoms in the DSM-IV – Do not mean

• Unable to focus…as in holding the camera still to take a photo of an unmoving object

– Do mean• Unable to focus…as in focusing on the task of

driving a car.

Development of Brain Structures that Support EF

Structures and functions that support EF are not fully developed at birth

Neural networks underlying EF control begin at 2-4 years of age, but don’t fully develop until the 20’s.

Development of EF capacities continues into early adulthood.

Continuing Brain Development in Late Childhood and Adolescence

6-15 years of age: extreme growth (80%) occurs at the collosal isthmus that supports associative relay, while considerable synaptic pruning occurs

Brain myelination increases 100% during the teenage years

Dopamine (DA), norepinephrine (NE) and Serotonin (5-HT) transmitter systems in the brain continue to develop into one’s 20’s

EF: Development & Demands

EF capacity develops through childhood/teens to adulthood – it is not totally present in early childhood.

Environmental demands for EF increase with age

EF impairments are frequently unnoticeable by age 7

How can EF become impaired?

Developmentally (eg, ADHD etc.) Trauma (eg, TBI) Disease (eg, Alheimer’s) In trauma & disease, the patient usually

has adequate EF, then loses it. In ADHD, EF has not developed

adequately.

Diagnosing ADHD: DSM-IV Inattentiveness:

Has a minimum of 6 symptoms regularly for the past six months.

Symptoms are present at abnormal levels for stage of development

Lacks attention to detail; makes careless mistakes

has difficulty sustaining attention

doesn’t seem to listen

fails to follow through/fails to finish projects

has difficulty organizing tasks

avoids tasks requiring mental effort

often loses items necessary for completing a task

easily distracted

is forgetful in daily activities

Diagnosing ADHD: DSM-IV

Hyperactivity/ Impulsivity:

Fidgets or squirms excessively

leaves seat when inappropriate

runs about/climbs extensively when inappropriate

has difficulty playing quietly

often “on the go” or “driven by a motor”

talks excessively

blurts out answers before question is finished

cannot await turn

interrupts or intrudes on others

Has a minimum of 6 symptoms regularly for the past six months.

Symptoms are present at abnormal levels for stage of development

Diagnosing ADHD: DSM-IV

Additional Criteria:

Symptoms causing impairment present before age 7

Impairment from symptoms occurs in two or more settings

Clear evidence of significant impairment (social, academic, etc.)

Symptoms not better accounted for by another mental disorder

Problems of Diagnosis

Subjectivity of Criteria

Inconsistent evaluations--presence of symptoms usually given by teacher or parent

Study by Szatmari et al (1989) showed that the number of diagnosed cases of ADHD decreased 80% when observations of parent, teacher and physician were used rather than just one source

Symptoms in females more subtle---leads to underdiagnosis

ADHD and the BrainDiminished arousal of the Nervous System

Decreased blood flow to prefrontal cortex and pathways connecting to limbic system (caudate nucleus and striatum)

PET scan shows decreased glucose metabolism throughout brain Comparison of normal brain (left) and brain

of ADHD patient.

ADHD and the Brain IISimilarities of ADHD symptoms to those from injuries and lesions of frontal lobe and prefrontal cortex

MRIs of ADHD patients show:Smaller anterior right frontal lobe

abnormal development in the frontal and striatal regions

Significantly smaller splenium of corpus callosumdecreased communication and processing of information between hemispheres

Smaller caudate nucleus

What causes ADHD?Underlying cause of these differences is still unknown; there is much conflicting data between studiesStrong evidence of genetic componentPredominant theory: Catecholamine neurotransmitter dysfunction or imbalance

decreased dopamine and/or norepinephrine uptake in braintheory supported by positive response to stimulant treatment

Recent study indicates possible lack of serotonin as a factor in mice

Dopamine in the Brain

Genetic Linkages to ADHD

Twin studies by Stevenson, Levy et al, and Sherman et al indicate an average heritability factor of .80Biederman et al reported a 57% risk to offspring if one parent has ADHD. Dopamine genes

DA type 2 geneDA transporter gene (DAT1)Dopamine receptor (DRD4, “repeater gene”) is over-represented in ADHD patients

DRD4

DRD4 is most likely contributor

DRD4 affects the post-synaptic sensitivity in the prefrontal and frontal cortex

This region of cortex affects executive functions and attention

Executive functions include working memory, internalization of speech, emotions, motivation, and learning of behavior

TreatmentCounseling of individual and family

Stimulants

Tricyclic antidepressants

Bupropion

Clonidine

SSRIs

Sedating Antihistamines

Benzodiazepines

-SNRI – atomoxetine HCL (Strattera)

StimulantsExact mechanism unknown

Raise activity level of the CNS by decreasing fluctuations of activity or lowering threshold needed for arousal

Similar in structure to NE and DA, and may mimic their actions

At least 75% have positive response with single dose

95% respond well to stimulant treatment

Include methylphenidate, dextroamphetamine, amphetamine-dextroamphetamine and pemoline

Methylphenidate

Is a piperidine derivative commonly known as Ritalin®

Is believed to act as dopamine agonist in synaptic cleft

Stimulates frontal-striatal regions

Dosage (5-20 mg) must be adjusted to each patient

Taken orally, 2-3 times a day as needed

Behavioral effects start within 1/2 hour to hour after ingestion, peaking at 1 and 3 hours

Also comes in Sustained-Release forms:

Concerta

Metadate

Effects of MPHElevates mood

Raises arousal of CNS and cerebral blood flow

Increases productivity

Improves social interactions

Increases heart rate and blood pressure

Side EffectsCommon:

decreased appetiteinsomniabehavioral reboundhead and stomach aches

Also thought to cause temporary height and weight suppression

Mild:anxiety/ depressionirritability

Rare:tics (Tourette’s Syndrome)overfocussingliver problems or rash (Pemoline only)

Storagevesicle

DA Transporter

Cytoplasmic DA

Methylphenidateinhibits

Presynaptic Neuron

Synapse

Probable Mechanism of Action of Methylphenidate

Wilens and Spencer. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501-513.

Neurotransmitters

CH2 CH2 NH2OH

OH

DopamineDopamineOH

CH CH NH2OH

OH

NorepinephrineNorepinephrine

CH2 CH NH2

CH3

AmphetamineAmphetamine

O

NH2

N

O

PemolinePemolineMethylphenidateMethylphenidate

COCH3

O

NH

MRI in Adults with ADHD

MGH-NMR Center & Harvard- MIT CITP

Bush G, et al. Biol Psychiatry. 1999;45(12):1542-1552.

Neurotransmitters

CH2 CH2 NH2OH

OH

DopamineDopamineOH

CH CH NH2OH

OH

NorepinephrineNorepinephrine

CH2 CH NH2

CH3

AmphetamineAmphetamine

O

NH2

N

O

PemolinePemolineMethylphenidateMethylphenidate

COCH3

O

NH

The Mechanisms of Action of AmphetamineThe Mechanisms of Action of AmphetamineWilens and Spencer. Handbook of Substance Abuse: Neurobehavioral Pharmacology. 1998;501-513.

AMPH Inhibits

AMPH is taken up into cell causing DA release into synapse

AMPH diffuses intovesicle causing DA release into cytoplasm

Presynaptic Neuron

Storagevesicle

DA TransporterProtein

Cytoplasmic DA

AMPH

AMPH

Synapse

AMPH blocks uptake into vesicle

Dopamine Neurotransmission Relative to ADHD

Enhances signal Improves attention

– Focus– On-task behavior– On-task cognition

Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

Nigrostriatal Pathway

Mesolimbic Pathway

Substantia nigra

Ventral tegmental area

Mesocortical Pathway

DopamineDopamine

Locus Ceruleus

Frontal

Limbic

Norepinephrine Neurotransmission Relative to ADHD

• Dampens noise

• Executive operations

• Increases inhibition

Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

NorepinephrineNorepinephrine

Catecholaminergic Neurotransmission Relative to ADHD

Striatal - Prefrontal Enhances Signal Improves Attention

– Focus– Vigilance– Acquisition – On-task behavior– On-task cognitive– Perception(?)

Prefrontal Dampens Noise

– Distractibility– Shifting

Executive operations Increases Inhibition

– Behavioral– Cognitive– Motoric

NorepinephrineNorepinephrineDopamineDopamine

Solanto. Stimulant Drugs and ADHD. Oxford; 2001.

MRI in Adults with ADHD

MGH-NMR Center & Harvard- MIT CITP

Bush G, et al. Biol Psychiatry. 1999;45(12):1542-1552.

Atomoxetine HCl

Strattera has recently been approved by the FDA as the only non-stimulant first line treatment for ADHD.

blocks norepinephrine transporter, especially in frontal lobes

no insomnia though some reduced weight gain with growth in first 12 months of use

non-controlled

Outcome ADHD can persist into adulthood, but usually symptoms

gradually diminish When it persists into adulthood, it usually requires ongoing

treatment and counseling most will develop another disorder (especially learning disability,

ODD, depression, and/or conduct disorder) Without treatment:

antisocial and deviant behavior increased rates of divorce, moving violations, incarceration,

and institutionalization