I



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

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

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)

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)

> 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

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)

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

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

Dopamine transporter gene (DAT1)

↑expression of the dopamine transporter

Results in ηre-uptake of dopamine out of synaptic cleft

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

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  

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 ≠  〈 function

Multimodal Treatment of ADHD Study (MTA)(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) = ηed benefit with sig. comorbidity(27)

Three year MTA follow-up has revealed (48)

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? 

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

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:

Risk factors for SUD

Retrospective studies suggest: ADHD ηed in adolescents and adults with SUD (30-35)

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

Via early expression of antisocial behavior(36)

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

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

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

Unmedicated children with ADHD  = ηed risk for SUD (44-46)

ADHD compared to controls report using substances  to

Attenuate mood

ι 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 ιes 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)

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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