ADHD Subtypes and Subgroups at Risk for Substance Use Disorders

1
ADHD Subtypes and Subgroups at Risk for Substance
Use Disorders

• Naimah Weinberg, M.D., Discussant
• Medical Officer
• National Institute on Drug Abuse, NIH

2
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

3
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?

4
Is ADHD a risk factor for SUD?

• Many clinical studies and reports suggest it is
• HOWEVER
• Not population based (referral bias)
• Some didnt take comorbidity into account
• Many are retrospective (subject to systematic
  recall bias)

5
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

6
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

7
Comorbidity

•  Is very common in children with ADHD
• Often associated with worse outcomes
• Numerous studies factoring in CD -gt 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

8
Is ADHD a risk factor for SUD? II

• Many clinical studies and reports suggest it is
• HOWEVER
• Not population based (referral bias)
• Some didnt take comorbidity into account
• Many are retrospective (subject to recall bias)
• So it isnt yet clear

9
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

10
Which children might be at increased risk?
(cont)

• 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

11
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

12
Why might some be at increased risk for SUD?
(cont)

• 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

13
Why might some be at increased risk for SUD?
(cont)

• 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-medicati
  ng late-onset subtype?
• Perhaps sensitization through use of stimulants

14
Why might some be at increased risk for SUD?
(cont)

• 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)

15
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

16
Does stimulant treatment alter the risk for SUD?

• Prescription stimulants
• Methylphenidate (Ritalin)
• Amphetamines (Dexedrine, Adderall)
• Pemoline (Cylert)
• Prescription estimates
• 3 - gt6 of American schoolchildren
• How they act release and/or block reuptake of
  dopamine into presynaptic neuron

17
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)

18
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

19
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 -gt 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

20
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

21
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

22
Does stimulant treatment alter the risk for SUD?
VII

• Animal studies weaknesses
• Rats dont have ADHD
• Rats lack human prefrontal cortex
• Medication not administered orally
• Outcome measures open to interpretation
• Volkow Insel, 2003 Hyman, 2003

23
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

24
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

25
Sources of divergence

• Methodologic measures, samples (self-selection),
  constructs, covariates, timing, length of follow
  up
• Individual factors stimulant exposure, family
  history, comorbidity

26
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

27
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

28
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