TITLE: Attention Deficit Hyperactivity Disorder—Its Treatment and Relationship to
Substance Use Disorders < Slide 1>
Larry Gray, MD
AMSP
Introduction
Importance: explosion in stimulant prescriptions (1) < Slide 2>
Annual rates of stimulant production rose 740% from 1991 and 2000
Amphetamine (eg. Adderall) production has risen 25-fold
USA consumed 80% of methylphenidate (Ritalin) in 1999
Confusion abounds when the understanding of ADHD is based on rates of specific treatments
Lecture aims regarding Attention Deficit Hyperactivity Disorder < Slide 3>
Epidemiology + course
Diagnosis
Etiology
Treatment
Relationship to substance use disorders (SUD).
Key points < Slide 4>
Very common in the community (= 10% of boys)
Central problem = poor attention and impulsivity
Pharmacotherapy improves symptoms
ADHD treatment may protect from later SUD
ADHD Nomenclature < Slide 5>
“Moral deficit”
Early 1900’s struggled with disability
Focus on voluntary behavioral control
Term cast aside as stigmatizing
“Minimal brain disorder”
1930’s to 1960’s
Term adopted from autopsy studies and emerging X-ray technology
Subtle anatomic brain differences linked to disruptive behavior
Attention Deficit Disorder (ADD) / Attention Deficit Hyperactivity Disorder (ADHD) (Diagnostic and Statistical Manual or DSM)
1970’s to present
Core symptoms of inattention and impulsivity
Converging evidence from genetics and neuroanatomy supports
ADHD: Epidemiology and Natural History < Slide 6>
ADHD is very common (2):
6 - 9 % of school-aged children (boys and girls)
Teachers est. 12 % of elementary classroom (3)
Parents est. 7 % of elementary age children (3)
Child psychiatrist interview < 2 % (with restricted comorbidity)
National survey (NSCHN) (2003)(4)
First national sample for prevalence est.
National prevalence of 8 %
4.4 million school-aged children
Boys: 2.5 X’s > girls
10 % boys
4 % girls
Natural history < Slide 7>
Behavioral symptoms often identified at school
Peak prevalence: full diagnosis 9-12 years of age
Symptoms change and lessen with age (5, 6)
Hyperactive / impulsive symptoms lessen with age
Inattention symptoms do not decrease with age
Symptoms of other psychiatric disorders (eg. anxiety and conduct disorder) increase with age
65 % continue to have partial symptoms > 25 yrs
Consistent with lifelong chronic disorder
ADHD: Making the Diagnosis < Slide 9>
DSM-IV criteria (7) (must impair or cause intense distress)
Inattention (> 6 required) (not all listed on slide 9)
Inattention to details / careless mistakes
Difficulty sustaining attention
Seems to not listen
Fails to finish tasks
Difficulty organizing
Avoids tasks requiring sustained attention
Loses things
Easily distracted
Forgetful
Impulsivity / Hyperactivity (> 6 required) < Slide 10>
Impulsivity
Blurts out answers before question is finished
Difficulty waiting turn
Interrupts or intrudes on others
Hyperactivity
Fidgets
Unable to stay seated
Inappropriate running/climbing
Difficulty engaging in activities quietly
“On the go”
Talks excessively
Establishing Symptom Criteria (7) < Slide 11>
Persistent pattern ≠ comparable developmental level
Persisted > 6 months
Onset < age 7 years
Impairment in > 2 settings (eg., school and home)
Sig. impairment in social, academic, or occupational function
Not better explained by other dx (eg. conduct disorder (CD))
ADHD differential diagnosis includes: < Slide 12>
Age-appropriate high activity
Thyroid disorders
Hearing loss or vision problem
Sleep disorder
Trauma / severe neglect (stressors inducing ADHD sx) (8)
Learning disabilities or understimulation (high IQ)
ADHD co-morbidity in school age years < Slide 13>
One third have pure ADHD(9)
Almost two-thirds (64 %) had comorbid condition(9)
ODD alone 21 %
ODD = defiant behavior toward authority
Part of the disruptive behaviors spectrum
Anxiety and ODD 12%
Anxiety alone 10%
Conduct disorder 7 %
Pattern of rights of other are violated
Aggression to people, animals, property
Theft
Serious rule violation (ie. legal trouble)
Tic Disorder 10%
Mood disorder 4%
ADHD DSM –IV Subtypes <slide 14>
Predominantly Inattentive type
> 6 inattentive criteria
< 6 impulsive/hyperactive criteria
Meets impairment criteria
27 %
Predominantly Hyperactive/Impulsive type
> 6 impulsive/hyperactive criteria
< 6 inattentive criteria
Meets impairment criteria
18 %
ADHD Combined type
> 6 inattentive criteria
> 6 impulsive/hyperactive criteria
Meets impairment criteria
55%
Diagnostic Limitations
ADHD is profile of behaviors
Diagnosis is based on clinical history which can be subjective
Symptoms are difficult to distinguish from normal behavior
Temperament or individual differences is hard to assess
DSM –IV
No special category for severe cormorbidities like conduct disorder
Allows conduct disorder as comorbid condition like anxiety or major depression
Other diagnostic systems (used in Europe for example) use conduct disorder as basis for main subdivision
Aims to recognize as many diagnoses as symptoms permit
Results in a broad range of symptoms in ADHD diagnosis
Clinical presentation of ADHD <slide 15>
Most frequently present for eval. at 6 – 12 yrs (5)
Variety of behavioral symptoms(10)
Distracted
Too talkative
Described as “immature” – acts younger than chrono. age
History of repeating a grade
Presentation in the adolescent (12 – 18 yrs) <slide 16>
Inner sense of restlessness rather than hyperactivity
Organization becomes priority in school work
“Executive” or managing skills get overwhelmed (11)
Driving skills reveal “executive” impairment (ADHD vs. non-ADHD) <slide 17>
> 12 moving violations ( 20 % vs 3 %)
> 5 speeding tickets (21 % vs 3 %)
> 3 car accidents ( 27 % vs 9 % )
ADHD = 3 X’s the dollar amount in damages
Pathophysiology of ADHD <slide 19>
Searches for biological basis to explain neuropsychological impairments
Anatomical abnormalities in frontal lobes and basal ganglia
Genetic molecular differences in the dopamine neurochemical pathways
Environmental risk factors that may stress developing CNS
Environmental /acquired risk may damage developing neurons(17) <slide 20>
Prenatal factors related to decreased fetal well-being
Low birth weight
Exposure to alcohol
Exposure to nicotine
Postnatal factors
CNS infections and trauma
Environmental lead exposure
Severe marital discord
Maternal mental health disorder
Not the focus of this talk
Genetic influences <slide 21>
Twin Studies
Heritability estimate from frequency of ADHD in twins
Monozygotic (identical) twins – 100% of their genes
Fraternal (dizygotic) twins – 50 % shared genes
Identical twins have > concordance than fraternal twins
0.50 -.0.76 for dizygotic
0.80 – 0.98 for monozygotic
Mean heritability estimate = 76%(18)
Molecular genetic studies
7 candidate genes emerged from twin studies (18)
Top gene candidates are dopamine D4 receptor (DRD4) and dopamine transporter gene (DAT1)
Dopamine D4 receptor (DRD4) gene is associated with a subsensitive postsynaptic receptor <slide 22>
Dopamine transporter gene (DAT1)
↑expression of the dopamine transporter
Results in hre-uptake of dopamine out of synaptic cleft <slide 22>
Supporting evidence
Animal studies: knockout mice lacking dopamine transporter
Have ↑ motor activity
Reduced locomotor response (19)
Mechanism of drugs used to treat ADHD (eg methylphenidate)
Blocks the dopamine transporter
Causes an accumulation of dopamine in synaptic cleft
Caution must be used in translating any genetic / anatomic study to DSM-IV ADHD phenotype (see diagnostic limitations)
Treatment of ADHD <slide 24>
Proven effective therapies
Therapy based on behavioral principles
Pharmacotherapy
Combination therapy
Behavioral Therapy(20)
Based on use of rewards and consequences
Uses behavioral techniques of reinforcement and punishment
Examples:
Behavioral parent training
Behavioral classroom training
Not effective: nonspecific family, individual, or cognitive therapies
Pharmacotherapy <slide 25>
Stimulants
Methylphenidate (Ritalin®) (eg. 5 to 20 mg three times a day)
D-amphetamine salts (Adderall®) (eg. 5 to 15 mg three times a day)
Once-a-day dosing increases compliance and decreases missed doses
Methylphenidate = Concerta ®
D-amphetamine salts = Adderall XR ®
Acts similar to cocaine
Similar chemical structure (21-23)
Enters brain more slowly
Less addictive potential (less reinforcing) (24)
Successful tx = rating scales = low or ‘0’ behaviors 25 = “normalized”
Controlling symptoms ≠ á function
Multimodal Treatment of ADHD Study (MTA)(26) <slide 26>
Success rates approach 90% with two main stimulants (27)
Clinically meaning benefits = ↓ in impairment
Benefits are quick to appear (ie days to weeks)
Behavioral therapy (BT) not as effective as stimulant meds only(27)
Intensive BT expensive
Intensive BT not widely available
Benefits take longer to appear (weeks to months)
Multimodal treatment (Meds + BT) = hed benefit with sig. comorbidity(27)
Three year MTA follow-up has revealed (48)<slide 27>
83% followed up; now 10-13 years old
MTA medication treatment groups (Meds + Comb) lost advantage
All 4 study groups show age-related ADHD symptom decline
Can stimulant medications be stopped? <slide 28>
Did children doing well stop meds?
Did children doing poorly start meds?
ADHD and Substance Use Disorders—A Complex Relationship
Adolescent Substance Use—Monitoring the Future Study <slide 30>
Annual nationwide survey of behaviors and attitudes in teens
2005 data from 50,000 8th, 10th, 12th graders
50% high school seniors = alcohol use in last month; 25 % = tobacco
“Some” illicit drug use: 25 % of high school seniors
accessed at: http://www.monitoringthefuture.org/
Risk factors for SUD
Retrospective studies suggest: ADHD hed in adolescents and adults with SUD (30-35)<slide 30>
Up to 50 % of adolescents with SUD have ADHD
25% of adults with SUD have ADHD
Development of conduct disorder mediates risk of alcohol use disorders <slide 31>
Via early expression of antisocial behavior(36) <slide 32>
ADHD w/o CD is ≠↑ risk for future antisocial behaviors(37)
SUD has 2 year earlier onset in ADHD compared to those without ADHD (38)
Persistence of symptoms in adolescence ↑’s risk of alcohol use (39)
Alcohol abuse and dependence studies <slide 33>
All SUD not the same (eg nicotine ≠ alcohol dependence)
San Diego Prospective Study of Alcoholism
Study of genetic and environmental influences in alcoholism
165 children of sons of alcoholics (ie. family history of AUD)
Now 14-25 years of age (separated into two groups)
Group 1 ( + CD or + ADHD)
Group 2 ( absence of CD or ADHD)
Results of comparison
Family Hx of AUD ≠ predict ADHD or CD
CD strongly correlated to SUD (18X’s Risk)
ADHD (w/o CD) did not inc risk for SUD
ADHD Studies of SUD <slide 34>
ADHD with comorbidity (eg. conduct disorder) ↑↑ risk of SUD
Accelerates the development to more severe SUD
Persistence of ADHD symptoms in adolescence(39)
ADHD persisters with no conduct disorder
2.5 X’s > risk of Alcohol Problem Score > 1
3 X’s > to be drunk 2 times or > in past 6 mths
ADHD persisters with conduct disorder
5 X’s > risk of Alcohol Problem Score > 1
4 X’s > to be drunk 2 times or > in past 6 mths
Persistence and severity of ADHD symptoms → alcohol misuse
Inattention symptoms predict better than childhood antisocial behaviors
Poorer scores on tests of attention were prospectively associated with greater substance use frequency(40)
Emerging relationship of treatment of ADHD to SUD <slide 35>
Unmedicated children with ADHD = hed risk for SUD (44-46)
ADHD compared to controls report using substances to
Attenuate mood
i Restlessness
Assist with sleep (35)
Meta-analysis of 12 studies : stimulant treatment does not lead to SUD in adults (21)
Early medication treatment for ADHD matters
Meta-analysis of 6 studies: Tx significantly ies the risk for subsequent SUD
Pharmacotherapy of ADHD= 85% ↓ risk for SUD in ADHD youth (45, 47)
3-fold decreased risk for SUD outcome in substance and alcohol(46) <slide 36>
75 % of unmedicated ADHD → SUD
25 % of medicated ADHD → SUD
Medicated ADHD same SUD rate as controls
Summary (We have reviewed:)
ADHD is very common (= 10% of boys)
Central problem = poor attention and impulsivity
Pharmacotherapy improves symptoms
ADHD treatment may protect from later SUD
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