Attention-Deficit Hyperactivity Disorder

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Attention-Deficit Hyperactivity Disorder
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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.

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Psychiatric Comorbidity
Anxiety (34)
MD (20 to 30)
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7
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CD (8 20)
Non-comorbid (55)
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ADHD Etiology

• ADHD is a heterogeneous behavioral disorder with
  multiple possible etiologies

Genetic origins
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Its a guy thing.
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ADHD Adult Common Comorbid Diagnosis
Male
Female
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Risk Factors for ADHD
Boys
Girls
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History of ADHD

• Mid-1800s Minimal Brain Damage
• Mid 1900s Minimal Brain Dysfunction
• 1960s Hyperkinesia
• 1980 Attention-Deficit Disorder
• With or Without Hyperactivity
• 1987 Attention Deficit Hyperactivity Disorder
• 1994-present ADHD
• Primarily Inattentive
• Primarily Hyperactive
• Combined Type

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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 conceptthere 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

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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

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Focus and Executive Functioning

• Intention symptoms in the DSM-IV
• Do not mean
• Unable to focusas in holding the camera still to
  take a photo of an unmoving object
• Do mean
• Unable to focusas in focusing on the task of
  driving a car.

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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 dont fully develop until
  the 20s.
• Development of EF capacities continues into early
  adulthood.

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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 ones 20s

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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

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How can EF become impaired?

• Developmentally (eg, ADHD etc.)
• Trauma (eg, TBI)
• Disease (eg, Alheimers)
• In trauma disease, the patient usually has
  adequate EF, then loses it.
• In ADHD, EF has not developed adequately.

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Diagnosing ADHD DSM-IV

• Lacks attention to detail makes careless
  mistakes
• has difficulty sustaining attention
• doesnt 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

• Inattentiveness
• Has a minimum of 6 symptoms regularly for the
  past six months.
• Symptoms are present at abnormal levels for stage
  of development

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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
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Diagnosing ADHD DSM-IV

• 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

• Additional Criteria

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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

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ADHD and the Brain

• Diminished 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.
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ADHD and the Brain II

• Similarities 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 callosum
• decreased communication and processing of
  information between hemispheres
• Smaller caudate nucleus

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What causes ADHD?

• Underlying cause of these differences is still
  unknown there is much conflicting data between
  studies
• Strong evidence of genetic component
• Predominant theory Catecholamine
  neurotransmitter dysfunction or imbalance
• decreased dopamine and/or norepinephrine uptake
  in brain
• theory supported by positive response to
  stimulant treatment
• Recent study indicates possible lack of serotonin
  as a factor in mice

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Dopamine in the Brain
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Genetic Linkages to ADHD

• Twin studies by Stevenson, Levy et al, and
  Sherman et al indicate an average heritability
  factor of .80
• Biederman et al reported a 57 risk to offspring
  if one parent has ADHD.
• Dopamine genes
• DA type 2 gene
• DA transporter gene (DAT1)
• Dopamine receptor (DRD4, repeater gene) is
  over-represented in ADHD patients

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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

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Treatment

• Counseling of individual and family
• Stimulants
• Tricyclic antidepressants
• Bupropion
• Clonidine
• SSRIs
• Sedating Antihistamines
• Benzodiazepines
• -SNRI atomoxetine HCL (Strattera)

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Stimulants

• Exact 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

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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

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Effects of MPH

• Elevates mood
• Raises arousal of CNS and cerebral blood flow
• Increases productivity
• Improves social interactions
• Increases heart rate and blood pressure

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Side Effects

• Common
• decreased appetite
• insomnia
• behavioral rebound
• head and stomach aches
• Also thought to cause temporary height and weight
  suppression

• Mild
• anxiety/ depression
• irritability
• Rare
• tics (Tourettes Syndrome)
• overfocussing
• liver problems or rash (Pemoline only)

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Probable Mechanism of Action of
MethylphenidateWilens and Spencer. Handbook of
Substance Abuse Neurobehavioral Pharmacology.
1998501-513.
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Neurotransmitters
Dopamine
Norepinephrine
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MRI in Adults with ADHD
MGH-NMR Center Harvard- MIT CITP
Bush G, et al. Biol Psychiatry.
199945(12)1542-1552.
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Neurotransmitters
Dopamine
Norepinephrine
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(No Transcript)
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The Mechanisms of Action of AmphetamineWilens
and Spencer. Handbook of Substance Abuse
Neurobehavioral Pharmacology. 1998501-513.
AMPH diffuses into vesicle causing DA release
into cytoplasm
AMPH blocks uptake into vesicle
AMPH is taken up into cell causing DA release
into synapse
AMPH Inhibits
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Dopamine Neurotransmission Relative to ADHD
Dopamine
Nigrostriatal Pathway

• Enhances signal
• Improves attention
• Focus
• On-task behavior
• On-task cognition

Mesolimbic Pathway
Substantia nigra
Mesocortical Pathway
Ventral tegmental area
Solanto. Stimulant Drugs and ADHD. Oxford 2001.
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Norepinephrine Neurotransmission Relative to ADHD
Norepinephrine

• Dampens noise
• Executive operations
• Increases inhibition

Solanto. Stimulant Drugs and ADHD. Oxford 2001.
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Catecholaminergic Neurotransmission Relative to
ADHD
Norepinephrine
Dopamine

• Prefrontal
• Dampens Noise
• Distractibility
• Shifting
• Executive operations
• Increases Inhibition
• Behavioral
• Cognitive
• Motoric

• Striatal - Prefrontal
• Enhances Signal
• Improves Attention
• Focus
• Vigilance
• Acquisition
• On-task behavior
• On-task cognitive
• Perception(?)

Solanto. Stimulant Drugs and ADHD. Oxford 2001.
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MRI in Adults with ADHD
MGH-NMR Center Harvard- MIT CITP
Bush G, et al. Biol Psychiatry.
199945(12)1542-1552.
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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

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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