TITLE:  Attention Deficit Hyperactivity Disorder—Its Treatment and Relationship to   

   Substance Use Disorders < Slide 1>


Larry Gray, MD



I.       Introduction

A.     Importance: explosion in stimulant prescriptions (1) < Slide 2>

1.      Annual rates of stimulant production rose 740% from 1991 and 2000

2.      Amphetamine (eg. Adderall) production has risen 25-fold

3.      USA consumed 80% of methylphenidate (Ritalin) in 1999

4.      Confusion abounds when the understanding of ADHD is based on rates of specific treatments

B.     Lecture aims regarding Attention Deficit Hyperactivity Disorder  < Slide 3>

1.      Epidemiology + course

2.      Diagnosis

3.      Etiology

4.      Treatment

5.      Relationship to substance use disorders (SUD).

C.     Key points < Slide 4>

1.      Very common in the community (= 10% of boys)

2.      Central problem = poor attention and impulsivity

3.      Pharmacotherapy improves symptoms

4.      ADHD treatment may protect from later SUD


II.    ADHD Nomenclature < Slide 5>

A.     “Moral deficit”

1.      Early 1900’s struggled with disability

2.      Focus on voluntary behavioral control

3.      Term cast aside as stigmatizing

B.      “Minimal brain disorder”

1.      1930’s to 1960’s

2.      Term adopted from autopsy studies and emerging X-ray technology

3.      Subtle anatomic brain differences linked to disruptive behavior

C.     Attention Deficit Disorder (ADD) / Attention Deficit Hyperactivity Disorder (ADHD) (Diagnostic and Statistical Manual or DSM)

1.      1970’s to present

2.      Core symptoms of inattention and impulsivity

3.      Converging evidence from genetics and neuroanatomy supports

III. ADHD: Epidemiology and Natural History < Slide 6>

A.     ADHD is very common (2):

1.       6 - 9 % of school-aged children (boys and girls)

a)      Teachers est. 12 % of elementary classroom (3)

b)      Parents est. 7 % of  elementary age children (3)

c)      Child psychiatrist interview < 2 % (with restricted comorbidity)

2.      National survey (NSCHN) (2003)(4)

a)      First national sample for prevalence est.

b)      National prevalence of 8 %

(1)       4.4 million school-aged children

(2)       Boys: 2.5 X’s > girls

(3)       10 % boys

(4)       4 % girls

B.     Natural history < Slide 7>

1.      Behavioral symptoms often identified at school

2.      Peak prevalence: full diagnosis 9-12 years of age

3.      Symptoms change and lessen with age (5, 6)

a)      Hyperactive / impulsive symptoms lessen with age

b)      Inattention symptoms do not decrease with age

c)      Symptoms of other psychiatric disorders (eg. anxiety and conduct disorder) increase with age

4.      65 % continue to have partial symptoms > 25 yrs

5.      Consistent with lifelong chronic disorder

IV.  ADHD: Making the Diagnosis < Slide 9>

A.     DSM-IV criteria (7) (must impair or cause intense distress)

1.      Inattention (> 6 required) (not all listed on slide 9)

a)      Inattention to details / careless mistakes

b)      Difficulty sustaining attention

c)      Seems to not listen

d)      Fails to finish tasks

e)      Difficulty organizing

f)        Avoids tasks requiring sustained attention

g)      Loses things

h)      Easily distracted

i)        Forgetful


2.      Impulsivity / Hyperactivity (> 6 required) < Slide 10>

a)      Impulsivity

(1)       Blurts out answers before question is finished

(2)       Difficulty waiting turn

(3)       Interrupts or intrudes on others

b)      Hyperactivity

(1)       Fidgets

(2)       Unable to stay seated

(3)       Inappropriate running/climbing

(4)       Difficulty engaging in activities quietly

(5)       “On the go”

(6)       Talks excessively

3.      Establishing Symptom Criteria (7) < Slide 11>

a)      Persistent pattern ≠ comparable developmental level

b)      Persisted > 6 months

c)      Onset < age 7 years

d)      Impairment in > 2 settings (eg., school and home)

e)      Sig. impairment in social, academic, or occupational function

f)        Not better explained by other dx (eg. conduct disorder (CD))

B.     ADHD differential diagnosis includes: < Slide 12>

a)      Age-appropriate high activity

b)      Thyroid disorders

c)      Hearing loss or vision problem

d)      Sleep disorder

e)      Trauma / severe neglect  (stressors inducing ADHD sx) (8)

f)        Learning disabilities or understimulation (high IQ)

C.     ADHD co-morbidity in school age years < Slide 13>

1.      One third have pure ADHD(9)

2.      Almost two-thirds (64 %) had comorbid condition(9)

a)      ODD alone 21 %

(1)       ODD = defiant behavior toward authority

(2)       Part of the disruptive behaviors spectrum

b)      Anxiety and ODD 12%

c)      Anxiety alone 10%

d)      Conduct disorder 7 %

(1)       Pattern of rights of other are violated

(2)       Aggression to people, animals, property

(3)       Theft

(4)       Serious rule violation (ie. legal trouble)

e)      Tic Disorder 10%

f)        Mood disorder 4%

D.    ADHD DSM –IV Subtypes <slide 14>

1.      Predominantly Inattentive type

a)      > 6 inattentive criteria

b)      < 6 impulsive/hyperactive criteria

c)      Meets impairment criteria

d)      27 %

2.      Predominantly Hyperactive/Impulsive type

a)      > 6 impulsive/hyperactive criteria

b)      < 6 inattentive criteria

c)      Meets impairment criteria

d)      18 %

3.      ADHD Combined type

a)      > 6 inattentive criteria

b)      > 6 impulsive/hyperactive criteria

c)      Meets impairment criteria

d)      55%


E.     Diagnostic Limitations

1.      ADHD is profile of behaviors

a)      Diagnosis is based on clinical history which can be subjective

b)      Symptoms are difficult to distinguish from normal behavior

c)      Temperament or individual differences is hard to assess

2.      DSM –IV

a)      No special category for severe cormorbidities like conduct disorder

b)      Allows conduct disorder as comorbid condition like anxiety or major depression

(1)       Other diagnostic systems (used in Europe for example) use conduct disorder as basis for main subdivision

c)      Aims to recognize as many diagnoses as symptoms permit

d)      Results in a broad range of symptoms in ADHD diagnosis


F.      Clinical presentation of ADHD <slide 15>

1.      Most frequently present for eval. at 6 – 12 yrs (5)

a)      Variety of behavioral symptoms(10)  

(1)       Distracted

(2)       Too talkative

b)      Described as “immature” – acts younger than chrono. age

c)      History of repeating a grade

2.       Presentation in the adolescent (12 – 18 yrs) <slide 16>

a)      Inner sense of restlessness rather than hyperactivity

b)      Organization becomes priority in school work

c)      “Executive” or managing skills get overwhelmed (11)

d)      Driving skills reveal “executive” impairment (ADHD vs. non-ADHD) <slide 17>

(01)           > 12 moving violations ( 20 % vs 3 %)

(02)           > 5 speeding tickets (21 % vs 3 %)

(03)           > 3 car accidents ( 27 % vs 9 % )

(04)           ADHD = 3 X’s the dollar amount in damages


V.     Pathophysiology of ADHD <slide 19>

A.     Searches for biological basis to explain neuropsychological impairments

1.      Anatomical abnormalities in frontal lobes and basal ganglia

2.      Genetic molecular differences in the dopamine neurochemical pathways

3.      Environmental risk factors that may stress developing CNS


B.     Environmental /acquired risk may damage developing neurons(17) <slide 20>

1.      Prenatal factors related to decreased fetal well-being

a)      Low birth weight

b)      Exposure to alcohol

c)      Exposure to nicotine

2.      Postnatal factors

a)      CNS infections and trauma

b)      Environmental lead exposure

c)      Severe marital discord

d)      Maternal mental health disorder

3.      Not the focus of this talk

C.     Genetic influences <slide 21>

1.      Twin Studies

a)      Heritability estimate from frequency of ADHD in twins

(1)       Monozygotic (identical) twins – 100% of their genes

(2)       Fraternal (dizygotic) twins – 50 % shared genes

b)      Identical twins have  > concordance than fraternal twins

(1)       0.50 -.0.76 for dizygotic

(2)       0.80 – 0.98 for monozygotic

c)      Mean heritability estimate = 76%(18)

2.      Molecular genetic studies

a)      7 candidate genes emerged from twin studies (18)

b)      Top gene candidates are dopamine D4 receptor (DRD4) and dopamine transporter gene (DAT1)

(1)       Dopamine D4 receptor (DRD4) gene is associated with a subsensitive postsynaptic receptor <slide 22>

(2)       Dopamine transporter gene (DAT1)

(a)    ↑expression of the dopamine transporter

(b)   Results in hre-uptake of dopamine out of synaptic cleft <slide 22>

3.      Supporting evidence

a)      Animal studies:  knockout mice lacking dopamine transporter

(1)       Have ↑ motor activity

(2)       Reduced locomotor response (19)

b)      Mechanism of  drugs used to treat ADHD (eg methylphenidate)

(1)       Blocks the dopamine transporter

(2)       Causes an accumulation of dopamine in synaptic cleft

c)      Caution must be used in translating any genetic / anatomic study to DSM-IV ADHD phenotype (see diagnostic limitations)

VI.  Treatment of ADHD <slide 24>

A.     Proven effective therapies

1.      Therapy based on behavioral principles

2.      Pharmacotherapy

3.      Combination therapy

B.     Behavioral Therapy(20)

1.      Based on use of rewards and consequences

2.      Uses behavioral techniques of reinforcement and punishment

3.      Examples:

a)      Behavioral parent training

b)      Behavioral classroom training

4.      Not effective: nonspecific family, individual, or cognitive therapies

C.     Pharmacotherapy <slide 25> 

1.      Stimulants

a)      Methylphenidate (Ritalin®) (eg. 5 to 20 mg three times a day)

b)      D-amphetamine salts (Adderall®) (eg. 5 to 15 mg three times a day)

c)      Once-a-day dosing increases compliance and decreases missed doses

(1)       Methylphenidate = Concerta ®

(2)       D-amphetamine salts = Adderall XR ®

2.      Acts similar to cocaine

a)      Similar chemical structure (21-23)

b)      Enters brain more slowly

c)      Less addictive potential (less reinforcing) (24)

3.      Successful tx =  rating scales = low or ‘0’ behaviors 25 = “normalized”

4.      Controlling symptoms ≠  á function


D.    Multimodal Treatment of ADHD Study (MTA)(26) <slide 26>

1.      Success rates approach 90% with two main stimulants (27)

a)      Clinically meaning benefits = ↓ in impairment

b)      Benefits are quick to appear (ie days to weeks)

2.      Behavioral therapy (BT) not as effective as stimulant meds only(27)

a)      Intensive  BT expensive

b)      Intensive BT not widely available

c)      Benefits take longer to appear (weeks to months)

3.       Multimodal treatment (Meds + BT) = hed benefit with sig. comorbidity(27)

4.      Three year MTA follow-up has revealed (48)<slide 27>

a)      83% followed up; now 10-13 years old

b)      MTA medication treatment groups (Meds + Comb)  lost advantage 

c)      All 4 study groups show age-related ADHD symptom decline

d)      Can stimulant medications be stopped?  <slide 28>

(1)       Did children doing well stop meds?

(2)       Did children doing poorly start meds?

VII.           ADHD and Substance Use Disorders—A Complex Relationship

A.     Adolescent Substance Use—Monitoring the Future Study <slide 30>

1.      Annual nationwide survey of behaviors and attitudes in teens

2.      2005 data from 50,000 8th, 10th, 12th graders

3.      50% high school seniors = alcohol use in last month; 25 % = tobacco

4.      “Some” illicit drug use: 25 % of high school seniors

5.      accessed at: http://www.monitoringthefuture.org/

B.     Risk factors for SUD

1.      Retrospective studies suggest: ADHD hed in adolescents and adults with SUD (30-35)<slide 30>

a)      Up to 50 % of adolescents with SUD have ADHD

b)      25% of adults with SUD have ADHD

2.      Development of conduct disorder mediates risk of alcohol use disorders <slide 31>

a)      Via early expression of antisocial behavior(36) <slide 32>

b)      ADHD w/o CD is ≠↑ risk for future antisocial behaviors(37)

3.      SUD has 2 year earlier onset in ADHD compared to those without ADHD (38)

4.      Persistence of symptoms in adolescence ↑’s risk of alcohol use (39)


C.     Alcohol abuse and dependence studies <slide 33>

a)      All SUD not the same (eg nicotine  ≠ alcohol dependence)

b)      San Diego Prospective Study of Alcoholism

(1)       Study of genetic and environmental influences in alcoholism

(2)       165 children of sons of alcoholics (ie. family history of AUD)

(3)       Now 14-25 years of age (separated into two groups)

(a)    Group 1 ( + CD or + ADHD)

(b)   Group 2 ( absence of CD or ADHD)

(4)       Results of comparison

(a)    Family Hx of AUD ≠ predict ADHD or CD

(b)   CD strongly correlated to SUD (18X’s Risk)

(c)    ADHD (w/o CD) did not inc risk for SUD


D.    ADHD Studies of SUD <slide 34>

1.      ADHD with comorbidity (eg. conduct disorder) ↑↑ risk of SUD

a)      Accelerates the development to more severe SUD

b)      Persistence of ADHD symptoms in adolescence(39)

(1)       ADHD persisters with no conduct disorder

(a)    2.5 X’s > risk of Alcohol Problem Score > 1

(b)   3 X’s > to be drunk 2 times or > in past 6 mths

(2)       ADHD persisters with conduct disorder

(a)    5 X’s > risk of Alcohol Problem Score > 1

(b)   4 X’s > to be drunk 2 times or > in past 6 mths

c)      Persistence and severity of ADHD symptoms → alcohol misuse

(1)       Inattention symptoms predict better than childhood antisocial behaviors

(2)       Poorer scores on tests of attention were prospectively associated with greater substance use frequency(40)


E.     Emerging relationship of treatment of ADHD to SUD <slide 35>

1.      Unmedicated children with ADHD  = hed risk for SUD (44-46)

2.      ADHD compared to controls report using substances  to


a)      Attenuate mood

b)      i Restlessness

c)      Assist with sleep (35)

3.      Meta-analysis of 12 studies : stimulant treatment does not lead to SUD in adults (21)

4.      Early medication treatment for ADHD matters

a)      Meta-analysis of  6 studies: Tx significantly ies the risk for subsequent SUD

b)      Pharmacotherapy of ADHD= 85% ↓  risk for SUD in ADHD youth (45, 47)

5.      3-fold decreased risk for SUD outcome in substance and alcohol(46) <slide 36>

a)      75 % of unmedicated ADHD → SUD

b)      25 % of medicated ADHD → SUD

c)      Medicated ADHD same SUD rate as controls

VIII.        Summary (We have reviewed:)

A.     ADHD is very common (= 10% of boys)

B.     Central problem = poor attention and impulsivity

C.     Pharmacotherapy improves symptoms

D.    ADHD treatment may protect from later SUD



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