ADHD: New Meds and New WrinklesLisa B. Namerow, M.D.Child and Adolescent PsychiatryHartford Hospital/Institute Of Living Mental Health

Network Associate Professor of Psychiatry and PediatricsUniversity of Connecticut School of MedicineMarch 29, 2012

Introduction• Although DMS-IV suggests that ADHD

symptoms must be present before age 7, they might not be observed or markedly interfere with functioning before developmental tasks exceed capabilities.

• For some, that might occur in preschool/grade school but for others, not until middle school, high school or beyond.

ADHD: Infant/Toddler Years

• history of excessive perinatal activity• difficult to soothe• high activity level, high distractibility• unable to sit in bouncy chair• “always on the go”• play more sensorimotor than

symbolic

Infant/Toddler Years (cont’d)

Treatment plan• anticipatory guidance• reroute energy• observe for other areas of

developmental difficulties(r/o PDD)• attempt to promote “goodness-of-fit” • Thwart ODD?

Infant and Toddler Pathways Leading to Early

Externalizing Disorders (JAACAP, 2001)

• Looked at high-risk children with low socioeconomic status

• At age 5.5, children with comorbid ADHD (ODD, ODD/CD) had mothers with more agression, depression and rejecting patterns of parenting

• ADHD alone showed no differences from the nonproblem children in terms of maternal characteristics or other risk factors

• Neuropsychological factors such as executive and verbal functioning deficits seem to add to risk

ADHD: Preschool Years• excessive motor activity• Play remains mechanical, motor-based

rather than • increasing need for high-stim

activities, frequent redirection• impulsivity can become a real problem• peer play can be impaired• aggression may become an issue

Treatment Plan: Preschool Years

• identify “profile”: hyperactive-impulsive versus inattentive

• access functional impairment: school, peers, family

• assess for comorbidities (ODD, anxiety• continue to discuss/recommend

behavioral interventions • consider pharmacotherapy if level of

impairment is marked

PATS Study (2006): Preschool ADHD Treatment

Study

• Designed to assess methylphenidate efficacy in preschool children

• Effect size in MTA .9-1.2 75-80%• Effect size in PATS (0.4-0.8)• in PATS, more side effects & intolerance (11%

discontinued) and impact on growth rates• All of which suggests a higher threshold for

pharmacotherapy

Treatment Plan (cont’d)• Remember: reducing hyperactivity/impulsivity

can help maintain developmental trajectory and reduce “failure”

• These children can often feel really bad about getting in trouble all the time

• Although “difficult” or “challenging”, they still need the same encouragement/support positive parental feedback but, it is occurs with much less frequency than “easy” temperament child

Comorbidities: Preschool Years

• r/o more global developmental disorders (MR, PDD’s)

• Consider other learning disorders (expressive language, executive functioning, other language-based or nonverbal (LDL)

• anxiety disorders • mood disorders (Bipolar or Unipolar))

ADHD: School Age (More Classic Presentation)

• 3 subtypes: hyperactive-impulsive, inattentive, combined-type

• use of behavioral checklists most appropriate

• Vanderbilt checklist approved by NICHQ & AAP

• Assess for comorbidity

DSM-IV Criteria for ADHDI. Either A or B:

Six or more of the following symptoms of inattention have been present for at least 6

months to a point that is disruptive and inappropriate for developmental level:

Inattention

Often does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities.

Often has trouble keeping attention on tasks or play activities.

Often does not seem to listen when spoken to directly.

Often does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions).

Often has trouble organizing activities.

Often avoids, dislikes, or doesn't want to do things that take a lot of mental effort for a long period of time (such as schoolwork or homework).

Often loses things needed for tasks and activities (e.g. toys, school assignments, pencils, books, or tools).

Is often easily distracted.

Is often forgetful in daily activities.

Six or more of the following symptoms of hyperactivity-impulsivity have been present for at least 6 months to an extent that is disruptive and inappropriate for developmental level:

Hyperactivity Often fidgets with hands or feet or squirms in seat.

Often gets up from seat when remaining in seat is expected.

Often runs about or climbs when and where it is not appropriate

(adolescents or adults may feel very restless).

Often has trouble playing or enjoying leisure activities quietly.

Is often "on the go" or often acts as if "driven by a motor". Often talks excessively.

(CONT’D)

DSM-IV Criteria for ADHDI. Either A or B:

Six or more of the followingOften blurts out answers before questions have been finished.

Often has trouble waiting one's turn.

Often interrupts or intrudes on others (e.g., butts into conversations or games).

Some symptoms that cause impairment were present before age 7 years.

Some impairment from the symptoms is present in two or more settings (e.g. at school/work and at home).

There must be clear evidence of significant impairment in social, school, or work functioning.

The symptoms do not happen only during the course of a Pervasive Developmental Disorder, Schizophrenia, or other Psychotic Disorder. The symptoms are not better accounted for by another mental disorder (e.g. Mood Disorder, Anxiety Disorder, Dissociative Disorder, or a Personality Disorder).

Based on these criteria, three types of ADHD are identified:

ADHD, Combined Type: if both criteria 1A and 1B are met for the past 6 months

ADHD, Predominantly Inattentive Type: if criterion 1A is met but criterion 1B is not met for the past six months 

ADHD, Predominantly Hyperactive-Impulsive Type: if Criterion 1B is

met but Criterion 1A is not met for the past six months.

American Psychiatric Association: Diagnostic and

Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000. [ADHD References]

The Vanderbilt Tool• health & history form for primary care• teacher’s checklist & parents checklist• initial screen includes comorbidities of

anxiety, ODD, mood (scoring easy!)• impact on learning also documented well• does not access for bipolar BUT if child

shows multiple comorbidities, consider bipolar

Vanderbilt (cont’d)

• follow-up checklists reference ADHD Sx’s alone• Scoring allows for identification of comorbidities

and differentiation of ADHD subtypes• What about discrepancy between teacher and

parent reports?• Anxiety can mediate impulsivity or hyperactivity

in unfamiliar settings• Remember: Final diagnosis is a clinical one; not

from a checklist alone

Comorbidity

• Anxiety Disorders• Mood disorders• Other disruptive behavior

disorders (ODD/CD)• Aggression• Tourette’s• Substance Use Disorders

Female Vs. Male ADHD

• Females tend to be more inattentive, less disruptive overall but social impact can still be significant

• On CPT testing, girls show less impulsivity (MTA, 2001)

• More associated with LD issues, but less ODD • even impulsivity can “look” different

associated with more “social butterfly chatter” rather than aggression or disruptive behaviors

• girls with ADHD have higher levels of anxiety, somatic sxs; boys have higher ODD/Conduct Disorders

Bipolar vs. ADHD

• Researchers believe that ADHD and Bipolar can be misdiagnosed symptom overlap but it is likely that there can be comorbidity as well

• In Bipolar children, rates of ADHD range 75-98% • In ADHD inpatients, 22% met criteria for Bipolar

(JACAAP, 1996)

• Nasreen et al., (2000) followed ADHD children into adulthood and noted much lower comorbidity

• Bottom line: the prevalence of ADHD is clearly much higher than Bipolar and therefore, when hyperactivity, impulsivity is present ADHD will be more likely

Bipolar vs. ADHD (cont’d)• Using a high index of suspicion, bipolar should

be considered when: -temper tantrums are marked often lasting 3-4

hours -thought process is markedly irrational, full of

violent content and/or threats and may contain hallucinations

• -speech is often pressured• -irritability is a marked finding• -there is a strong family history• -grandiosity, hypersexuality can be

differentiating symptoms (Geller, Carlson and others)

School Age: Treatment Plan

• MTA serves as guideline for treatment efficacy (See Dev and Behav Peds, Feb, 2001)

• 4 arms: CC, Medmgt, Beh, Comb• Medmgt, or Comb clearly superior• Comb had interesting effects over time but

was mediated by parental attitudes, strategies• pharmacotherapy clearly has EBM support for

ADHD (meeting full A-level criteria)

Assessment Points

Baseline EarlyTreatment(3 m)

Mid-treatment(9 m)

EndTreatment(14 m)

Follow-up(24 m)

Follow-up(36 m)

14-m Treatment Stage

10-m Follow-up AfterTreatment

22-m Follow-up AfterTreatment

0 362414

RecruitmentScreeningDiagnosis

RandomAssignment

579 ADHD Subjects

Medication Only144 Subjects

Psychosocial (Behavioral)Treatment Only144 Subjects

Combined Medication & Behavioral Treatment145 Subjects

Community ControlsNo Treatment from StudyAssessed for 24 mo.146 Subjects

Recruitment of LNCG Cohort

MTA Study

14-Month Outcomes 14-Month Outcomes Teacher SNAP-InattentionTeacher SNAP-Inattention

0

0.5

1

1.5

2

2.5

3

0 100 200 300 400

CC

Beh

MedMgt

Comb

Time x Tx: F=10.6, p<.0001Site x Tx: F=0.9, nsSite: F=2.7, p<.02

Comb, MedMgt > Beh, CC

Avera

ge S

core

Assessment Point (Days)

days

0.5

1

1.5

2

2.5

0 100 200 300 400

Assessment Point (Days)

Ave

rage

Sco

re

CC-NOMEDS

CC-MEDS

BEH

MED

COMB

Key Differences,

MedMgt vs. CC:

Initial Titration

Dose

Dose Frequency

#Visits/year

Length of Visits

Contact w/schools

Teacher-Rated InattentionTeacher-Rated Inattention(CC Children Separated By Med Use)(CC Children Separated By Med Use)

Nonpharmacologic Interventions

• family psychoeducation a must • behavior therapy should be

considered• Social skills training if social

competency are significant issues

ADHD and School• Impact on learning is quite variable

depending on aymptom impact• full psychoeducational evaluation if

learning below grade level• neuropsychological evaluation if

resources are present• 504 plan considered vs. IDEA

designation

Adolescent Years• often won’t meet the criteria of

“symptoms present since age 7” • clinical impact may not have been

apparent earlier because of higher IQ, better organizational skills

• now the “bar” for social & academic competence is higher and the “attentional deficit” is now having greater impact

• first presentation may be as a mood or anxiety disorder

Inattention SymptomsDSM-IVSymptom Domain• Difficult sustaining

attention• Does not listen• No follow-through• Cannot organize• Loses important items• Easily distractible and

forgetful

Common Adolescent/Adult Manifestations

• Poor time management• Difficult initiating/completing

tasks, changing to another task when multitasking, required

• Procrastination• Avoids tasks that demand

attention• Adaptive behavior-self select

lifestyle, support staff, ect.

Hyperactivity Symptoms

DSM-IVSymptom Domain• Squirms and fidgets• Cannot stay seated • Runs/climbs

excessively • Cannot play/work• “On the go”/”driven

by a motor”• Talks excessively

Common Adolescent/Adult Manifestations

• Adaptive behavior-working long hours, selects a lot of activities, multiple jobs, or a very active job

• Constant activity leading to family tension

• Avoids situations required low levers of activity because easily bored

• Symptoms often felt rather than manifested

Impulsivity SymptomsDSM-IVSymptom Domain• Blurts out answers• Cannot wait turn• Intrudes/interrupts

others

Common Adolescent/Adult Manifestations

• Low frustration tolerance –quitting a job, ending a relationship, losing temper, driving too fast

• Makes quick decisions• Interrupts

Common Comorbid Psychiatric Disturbances in Adolescents

with ADHDComorbidity Prevalence Among Prevalence in General

Adolescents With ADHD Adolescent Population

Academic 20-60% 5-15%Impairment___________________________________________Major depressive 9-32% {average 25%} 3-5%Disorder _________________________________________Anxiety disorder 10-40% {average 25%} 3-10%_________Conduct disorder 20-56% Unknown_______Oppositional 20-67% {average 35%} 2-16%{average7-8%}defiant disorder _______________________________________Bipolar disorder -6-10% 3-4%__________

ADHD=attention-deficit/hyperactivity disorder.

The “bio” part of a biopsychosocial treatment

plan• Considered along with school

support, outside support• Recent NY times article (2012)• Always consider nonpharmacologic

options first, or at least, along with• Utilize the EBM studies, PATS, MTA• Consider algorithms

Pediatric Psychopharmacology: Non-Diagnostic Considerations

• Compliance: Can this system (i.e., family and patient) comply with twice a day or three times a day dosing?

• Past Medical History (i.e., Is there a history of tics, liver disease, cardiac conduction abnormalities, seizures)

• Need for Medical Monitoring: Will it be a problem for this family if frequent blood drawing is needed?

• Is there potential for this patient or anyone in the family to use this medication as a substance for abuse?

• Is there a potential for this patient or anyone in the family to use this medication in a suicidal gesture?

New considerations:Genomic Testing

• P450 analysis on 3 isoenzymes has been developed• As a review, the P450 system is a series of enzymes in the

liver which break down “toxins”• The analysis is based on genomic technology and using

whole blood, determines the presence or absence of the allelles that promote the formation of these 3 enzymes

• In doing so, enzymes can be categorized as normal, deficient, null or ultrarapid in their activity

• It has been determined by very smart pharmacologists which medications are substrates for which enzymes---some medications can even induce or inhibit the activity of an enzyme

•

DNA-Guided Psychotropic Selection

Frequency of Polymorphisms

None

2C9

2D6

2C192D6

2C19

2C92C92C192C19

2C92D6

2C92C192D6

Single Gene Alterations46%

Double and Triple Gene Alterations45%

No Gene Alterations9%

N=577N=577LPH PatientLPH PatientReferralsReferralsNov. 2009Nov. 2009

THE STIMULANTS

Ritalin® LA: Extended-release Delivery via SODAS™

Technology

SODAS™ is a trademark of Elan Corporation, PLC

Long-acting Methylphenidate

Medications

Concerta® [package insert]. Moutain View, CA: Alza Corporation; 2001. OROS® is a registered trademark of ALZA Corporation.Metadate® CD [package insert]. Rochester, NY: Celltech Pharmaceuticals, Inc; 2002. Diffucaps® is a registered trademark of Eurand.Ritalin® LA [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2002. SODAS™ is a trademark of Elan Corporation, Plc.

Products Concerta® Metadate® CD Ritalin® LA

OROS® Diffucaps® SODAS™

Dose 18 mg 27 mg 36 mg 54 mg 20 mg 20 mg 30 mg 40 mg

Immediaterelease 4 mg 6 mg 8 mg 12 mg 6 mg 10 mg 15 mg 20 mg

30% 50%

Sustained/2nd release 14 mg 21 mg 28 mg 42 mg 14 mg 10 mg15 mg 20 mg

78% 70% 50%

22%

FormulationTechnology

Ritalin® LA 40 mg

Metadate® CD 60 mg (3 x 20 mg)

Concerta® 54 mg

Time (h)

0 5 10 150

5

10

15

20

Mea

n d,l

-met

hyl

ph

enid

ate

pla

sma

leve

ls (

ng

/mL

)

Comparison of Extended-release Methylphenidate

Dosage Forms

Ritalin® 20 mg BID

Gonzalez MA, et al. Int J Clin Pharmacol Ther. 2002;40:175-184.

Data on file, Novartis Pharmaceuticals.

Vyvanse• Not biologically active until cleaved

during the GI absorption process• Reportedly has a continuous absorption

that enhances duration of action• Can be swallowed whole or sprinkled in

water• Less rebound?

Daytrana• Transdermal absorption• Lasts 9 hours• Needs to be placed and removed

every day alternating sites• Less ups and downs?

Long-acting stimulants: The

good news• Less chance of abuse• Greater chance of compliance• Less chance of stigmatizing due to trips

to the school nurse• Less chance of rebound• Less chance of “ups and downs”

Long-Acting Stimulants: The Bad News

• May have greater potential for weight loss• May have greater potential for agitation: ?

More potent• May have greater chance for sleep

disturbance• Take home: tolerance of short-acting

stimulants does not assure tolerance of long-acting preparations but the long-acting agents offer some clear advantages if well-tolerated

The nonstimulants

Strattera: The first NRI• A completely different class of medication for

ADHD, a norepinephrine reuptake inhibiter• Not a controlled medication• The first nonstimulant approved by the FDA

for age 6 and over for ADHD• Works by establishing a steady state, so

needs to be taken daily rather than as needed• Yet, seems to have a rapid onset of action

Alpha 2 Agonists• Mechanism: alpha 2 stimulants cause

the presynaptic noradrenergic receptor to decrease sympathetic output over time, this is a brake on the release of norepinephrine.

• Approved for HTN in adults but used in children for treatment of tics, ADHD, and aggression.

Guanfacine ER (Intuniv)• A long acting version of Tenex• May have less sedation• FDA approved for ADHD in children

over 6• Would assess tolerance by using

short-acting first, then converting• Comes in 1mg, 2mg, 3mg, 4mg

Kapvay (clonidine)• FDA approved as an adjuvant to

stimulant meds• Dosed twice per day• Possibly less sedation than its

short acting version, clonidine

Medication Management: ADHD (Texas Algorithm, July, 2005)

•ADHD•ADHD with MDD

•ADHD with Anxiety•ADHD with tics

•ADHD with aggression

ADHD alone

ADHD with tics

ADHD with Aggression

Medical workup and monitoring

• EKG???: Let’s talk: JAACAP, October 2011)

• Baseline bp, pulse, ht, weight• Subsequent vital signs at each

visit• Impact on growth?: let’s talk again

Two Case Illustrations: Case #1

• 14 y/o male currently in 9th grade athletic, A-student presents for evaluation of “depression”

• History reveals 1-year history obsessional intrusive worries regarding academic work, tests, basketball practice

• MSE reveals almost rigidly anxious, tearful young man

Case #1 (cont’d) • parents revealed no past history or family

history initially but when questioned….psychologist saw pt in 7th grade for “ADHD”

• thought he met criteria, but parents felt it wasn’t an issue & grades were high

• also very (+) family history of OCD • diagnosis: OCD with underlying ADHD • treatment: target OCD first then ADHD

Case #2:Adolescent ADHD

• 13 y/o 8th grade female presented with grades, motivation, sadness• In reviewing all prior grades, there was no

history of learning or attentional difficultness by teacher comments or conferences

• when questioned, family did reference “she always has her head in the clouds” when she isn’t being a “social butterfly”

• DX: Depressive Disorder, NOS with R/O for ADHD

• TX: target depression first then ADHD

College - Age• May also be “first” presentation• With transition lack of home-based structure

support, need for higher-level executive functioning attentional symptoms may become first apparent

• Response to a friend’s Ritalin does not make the diagnosis but “might” suggest need for further review

• Would suggest a neuropsychological if adolescence or college is “first presentation” of ADHD and had never before been considered or documented

Take Home Points• although fairly straightforward in some

individuals, ADHD can be elusive in others• think developmentally • sometimes, symptoms are not clinically

apparent until the tasks become challenging enough

• some of these symptoms contribute to success given the demands of the 21st century (Does this then contribute to the promotion of the “genes”?)

Take home points (cont’d)

• Literature supports that the natural “untreated” course of ADHD places a child or adolescent at high risk for comorbidities such as substance use disorders, Anxiety, Depression, ODD/Conduct Disorder or a sense of “failure”

Take Home Points (con’t)

• Adults can often find a nitch that works for their individual strengths/weaknesses

• But the first 18-21 years of life can be a real challenge

• The push for identification and treatment of ADHD is NOT meant to simply pathologize normal variants of behavior but rather to promote an “at-risk” child’s developmental trajectory