ADHD Subtypes and Subgroups at Risk ADHD Subtypes and Subgroups at Risk for Substance Use Disordersfor Substance Use Disorders

Naimah Weinberg, M.D., DiscussantMedical Officer

National Institute on Drug Abuse, NIH

What is SUD?

Substance Use Disorder (abuse or dependence), per DSM

Distinct from substance use: while use appears driven by both biological and environmental factors, progression to abuse & dependence largely influenced by individual-level (genetic, psychiatric) factors

Difficult to apply to adolescents, but no current standardized substitute

Some studies use early onset drug use as proxy for SUD

Current research questions Is ADHD a risk factor for SUD?

Which children with ADHD might be at increased risk? for which substances?

Why might some children with ADHD be at increased risk for SUD?

Does treatment of ADHD alter risk for SUD?

Does stimulant treatment alter risk for SUD?

Is ADHD a risk factor for SUD?

Many clinical studies and reports suggest it is

HOWEVER: Not population based (referral bias)

Some didn’t take comorbidity into account

Many are retrospective (subject to systematic recall bias)

Population-based studies

  Population-(or community-)based studies are needed to validate clinical studies because:

Clinic samples more likely to include comorbidity

Clinic and community samples may differ in severity, comorbidity patterns, temporal ordering, risk factors, treatment history

Seeming risk factors for disorder may actually be markers of likelihood for referral (e.g. poverty and Medicaid) Armstrong & Costello, 2002

Population-based studies of ADHD and SUD

A few so far

Taken together, do not support ADHD as risk factor when CD is taken into account

Comorbidity

 Is very common in children with ADHD

Often associated with worse outcomes

Numerous studies: factoring in CD -> ADHD drops out as SUD risk factor

However, some recent literature finding a contribution of ADHD in presence of CD

Externalizing-internalizing combination also associated w/increased SUD risk

Is ADHD a risk factor for SUD? II

Many clinical studies and reports suggest it is

HOWEVER: Not population based (referral bias)

Some didn’t take comorbidity into account

Many are retrospective (subject to recall bias)

So it isn’t yet clear

Which children with ADHD might be at increased risk?

Clinically derived; may offer clues to further study

Comorbid psychiatric disorders

Family history of SUD (may contribute to both ADHD and SUD)

Persistent ADHD

Social skills deficits

Which children might be at increased risk? (con’t)

Severity of childhood symptoms?

Inattention (for tobacco)?

Impulsivity or disinhibition (for other drugs)?

Gender differences: findings contradictory so far

Ethnic or racial group differences: inadequately studied so far

Why might some with ADHD be at increased risk for

SUD?Biologically: mostly common risk factors, a few

mediators

Psychosocially/environmentally: mostly mediators between ADHD and (early) substance use

And these interact

Why might some be at increased risk for SUD? (con’t)

May both be manifestations of behaviorally disinhibited phenotype

Executive cognitive dysfunction present in ADHD and predicts SUD (in high risk samples)

Temperament: novelty seeking, low constraint – may mediate, maybe affect dysregulation

Why might some be at increased risk for SUD? (con’t)

Other biological associations: Through prenatal exposure to alcohol, smoking, perhaps drugs

Low birth weight

Dopaminergic system: Self-medication? (especially tobacco)

Perhaps an internalizing/inattentive/self-medicating late-onset subtype?

Perhaps sensitization through use of stimulants

Why might some be at increased risk for SUD? (con’t)

Psychosocial factors that might impact use/early use:

Weak attachment to & conflict with parents, school secondary to behavior problems

Disordered alcohol or drug expectancies

Association with deviant peers

Attribution (fulfilling expectations)?

Parental modeling, monitoring, coping (ADHD parents or child-induced)

Does treatment of ADHD alter the risk for SUD?

Little data so far

Focus of ongoing and new studies

However, controlled clinical studies lacking

Answers could help us disentangle etiologic role of ADHD in risk for drug abuse

Does stimulant treatment alter the risk for SUD?

Prescription stimulants: Methylphenidate (Ritalin)

Amphetamines (Dexedrine, Adderall)

Pemoline (Cylert)

Prescription estimates: 3% - >6% of American schoolchildren

How they act: release and/or block reuptake of dopamine into presynaptic neuron

Does stimulant treatment alter the risk for SUD? II

Why might stimulant medication increase risk for SUD?

Psychologically: engender drug-taking attitudes, use of drug to solve problems; reliance on medication reduces efforts to develop other coping mechanisms or pursue other treatments

Biologically: sensitization, i.e. persistent hypersensitivity to drug effects as result of prior exposure (both stimulants and drugs of abuse act through increased dopamine transmission)

Does stimulant treatment alter the risk for SUD? III

Why might stimulant medication reduce risk for SUD?

Psychologically: through improved self-esteem, academic achievement, relationships, parent monitoring

Biologically: reduce “self-medication”; may alter reinforcing properties of drugs; hypothesized that early stimulant treatment normalizes white matter volume, in turn enhancing executive function and reducing later SUD risk

Does stimulant treatment alter the risk for SUD? IV

Human follow up studies: findings Most show no effect or a protective effect Meta-analysis of 5 studies -> 2.3-fold reduced risk for SUD

associated with stimulant treatment in youth (Wilens et al, 2003)

However, some have found increased rates of SUD outcomes

“Protection” may depend on age at prescription, and may dissipate by adulthood

Does stimulant treatment alter the risk for SUD? V

Human follow up studies: weaknesses

NOT RANDOMIZED! Self-selection effects and biases: which children receive

medication may be function of factors that alter risk

Possible cohort effects on prescription patterns

Need to take into account age at prescription, age at assessment, length of follow up

Does stimulant treatment alter the risk for SUD? VI

Animal studies: findings Recent refinements studying pre- and peri-adolescent rats, using

therapeutic-range dosages of methylphenidate Show long-lasting behavioral and neurobiological adaptations, and

altered responses to reinforcing properties of cocaine in adulthood Results inconsistent: some show enhanced reinforcement by

cocaine, some reduced Response appears to be sensitive to age at administration: younger

reduces reinforcement

Does stimulant treatment alter the risk for SUD? VII

Animal studies: weaknesses Rats don’t have ADHD

Rats lack human prefrontal cortex

Medication not administered orally

Outcome measures open to interpretation

Volkow & Insel, 2003; Hyman, 2003

Does stimulant treatment alter the risk for SUD? VIII

Perhaps no single answer: impact on risk may depend on subtype, interaction with other risk and protective factors, age at medication administration, medication response, choice of stimulant

Or, no impact

Summary of the science

Lack population-based data supporting ADHD itself as a risk factor for drug abuse

Subgroups appear to be at increased risk: comorbid disorders esp. conduct, family history of drug abuse, perhaps more severe or impairing ADHD

Understanding impact of pharmacologic and behavioral treatments is important, controversial, and not yet clear

Sources of divergence

Methodologic: measures, samples (self-selection), constructs, covariates, timing, length of follow up

Individual factors: stimulant exposure, family history, comorbidity

State of research

Several NIDA-funded studies underway (many population-based) to address these questions

Data from studies funded by NIMH, NICHD, NIAAA might also be mined to address

For clinical (treatment) questions, data from controlled clinical trials are lacking; MTA may be opportunity

Public health implications

Major public health issues, given prevalence of ADHD, SUD, stimulant use, individual and social costs of these disorders

More work needed on all these questions

Ultimate goal: reduction and prevention of SUD and associated adverse outcomes

Public health implications II

For etiologic questions: require sophisticated transdisciplinary approaches, that nest imaging, neurocognitive tests, behavioral pharmacology, genetics research in studies of population-based samples

For treatment issues: need randomized studies (within ethical limits; MTA), prospective studies, creative methodologic approaches, developmental sensitivity, and to take family history of SUD into account

Etiologic and prevention research can and must be used to inform each other