Optimizing and Personalizing Treatment for ADHD

Margaret Weiss MD PhDProvincial ADHD Program

mweiss@cw.bc.ca

Remission

• Definitions of remission are all symptom based

• Much or very much improved on the CGI-I• Mean score on the ADHD RS of < or = 1• Two score change on CGI-S• These definitions are currently used in

efficacy studies: short term, non comorbid, protocol driven studies with full compliance

Chronic Developmental Disorders

• The concept of remission derives from depression work where it predicted the likelihood of ultimate outcome

• ADHD is a developmental disorder which waxes, wanes and changes with different developmental disorders

• Does remission make sense?

Correlation of ADHD symptoms to functioning

• .2 in most studies to .68Gordon, J Attn Dis 2008

• The patient: “Does he treat what I have?”– Impairment, poor quality of life, adaptive

skills• The doctor: “Does he have what I treat?”

– Diagnoses

1. Difficulty paying close attention to details or making careless

mistakes

0 1 2 3

2. Difficulty paying attention to tasks or fun activities 0 1 2 3

3. Difficulty listening when spoken to directly 0 1 2 3

4. Difficulty organizing tasks and activities 0 1 2 3

5. Difficulty following through on instructions and failing to finish

things

0 1 2 3

6. Avoiding doing tasks that require a lot of mental effort

(paperwork, rote learning, chores)

0 1 2 3

7. Losing things necessary for activities 0 1 2 3

8. Easily distracted 0 1 2 3

9. Forgetful in daily activities 0 1 2 3

SNAP INATTENTION www.adhd.net

SNAP IV: Hyperactive Impulsive

10. Fidgety and squirmy 0 1 2 3

11. Difficulty remaining seated 0 1 2 3

12. Feeling restless, or excessive running about 0 1 2 3

13. Difficulty engaging in leisure activities or doing fun things quietly

0 1 2 3

14. Always �on the go� or acting as if �driven by a motor� 0 1 2 3

15. Talking excessively 0 1 2 3

16. Blurting out answers to questions before they were completed

0 1 2 3

17. Difficulty awaiting turn 0 1 2 3

18. Interrupting people or intruding on others 0 1 2 3

WEISS FUNCTIONAL IMPAIRMENT RATING

• Parent Report; Adult Self Report• No symptom items• Public Domain www.caddra.ca• Translated 18 languages• Recommended and reproduced in the Canadian Practice

guidelines www.caddra.cA• Clinician friendly• CADDRA guidelines use both sx/fxn outcomes• Internal consistency >.8, factor confirmation, high

correlation to symptoms, high sensitivity to change

Psychometric Validation WFIRS1

• Chronbach’s alpha >.9• Chronbach’s alpha domains .75 - .93• Sensitivity to change > 40%• Effect size change ATX .7 – 1.2• Factor analysis validates domain structure but

learning and school behavior are distinct• QoL, Fxn, Sx are overlapping but distinct

concepts

1AACAP 2007

Correlations of ADHD, Academic, Cognitive, and Functional Outcomes1

• 105 children 8 – 11 y who were treatment naïve

• Treated with ATX x 1 year• Measured outcome using the ADHD-RS,

WJIII, BASC, WFIRS • Analyzed correlations between outcomes

Dickson, R., Weiss, M. AACAP 2007; CACAP 2007

Improvement

1. Symptoms2. Functional Impairment3. Quality of Life4. Adaptive Skills5. Cognition6. Developmental gains

ADHD Symptoms ADHD RSOne Year Outcomes 8 – 11 y ATX

�

0

5

10

15

20

25

30

35

40

45

0 2 4 6 8 10 12

Time (months)

Mea

n Sc

ore

(95%

CI)

Total ScoreInattentionHyperactivity/Impulsivity

WFIRS by Visit

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

Baseline Day 35 Day 63 Day 91

Visit

Mea

n

Overall

Family

Learning and School

Life Skills

Child's Self-Concept

Social Activities

Risky Activities

Results: Academics

2.6

-0.2

1.71.6

-2

-1

0

1

2

3

4

5

WJIII Total Broad Reading Broad Math Broad Written

Mea

n C

hang

e (9

5% C

I)

* *

*

- WJIII® Standard Scores: Change from Baseline to 1 Year

3.3*3.7

0.5

2.5*

-1.6-3.1*

0.2

1.91.7*

-6

-4

-2

0

2

4

6

8

Letter-WordIdentification

Reading Fluency PassageComprehension

Calculation Math Fluency Applied Problems Spelling Writing Fluency Writing Samples

Mea

n C

hang

e (9

5% C

I)

Executive Function: Brief

89.0

82.4

91.9

93.4

89.2

78.7

83.4

86.4

92.7

85.7

91.9

69.0

70.2

76.9

78.5

72.5

65.5

68.4

66.5

74.9

66.4

73.1

0 20 40 60 80 100

Global Executive Composite

Behavioral Regulation

Metacognition

Inhibit

Shift

Emotional Control

Initiate

Working Memory

Plan/Organize

Organization of Materials

Monitor

BRIEF Percentile Mean Score (95% CI)

Baseline (N=105) 1-Year (N=66)

Psychopathology: Behavior Assessment System

Children (BASC-PRF)

68.2

52.0

61.4

53.5

65.4

56.8

52.4

47.8

61.1

53.3

62.4

52.5 51.948.9

70.7

61.0

38.1

42.540.8

45.247.3

48.2

42.543.5

30

40

50

60

70

80

Hype

racti

vity

Aggr

essio

n

Cond

uct

Prob

lems

Anxie

ty

Depr

essio

n

Soma

tizati

on

Atyp

icality

With

draw

al

Atten

tion

Prob

lems

Ada

ptabil

ity

Socia

l Skil

ls

Lead

ersh

ip

BA

SC P

RS

T-Sc

ore

Mea

n (9

5% C

I)

Change in ADHD symptoms mediates*

• Overall functioning, home life, school, social, activities of daily living and risky activities on the WFIRS but has minimal impact on self concept

• Executive function: total score and all subscales on the BRIEF

• All subscales and adaptive skills• on the BASC child and parent report

*p < .05

Change in ADHD symptoms does not mediate

• Improvement in the WJIII raw scores (correlation .066, p = .6)

• Improvement in the WJIII standard scores• (correlation .007, p = .96)• There are modest improvements in WJIII

reading and writing, but math fluency declines

Correlations

• There is a statistically significant correlation between improvement in ADHD and improvement in functioning, quality of life, psychopathology, and strengths

• Although children improved academically when ADHD was treated this was not statistically correlated

QUEST

• Quality of life, effectiveness, safety and tolerability study of adults with ADHD

• 735 adults; 83 sites• Outcome of 30 weeks of MAS-XR as

measured by ADHD-RS-Inv, SF-36; AIM-A; and medication satisfaction

• HRQL improved cotemporous with symptoms, with increase mainly in emotional well being

Effectiveness Outcomes

• Compliance and persistence• Real life, comorbid, clinic patients with

complex psychosocial problems and ethnic backgrounds

• Cost• Broad based outcomes• Risk/benefit ratio of improvement and

deleterious side effects

Research on Effectiveness• Evidence based medicine means we are funnels

of information to assist patients with guided choices

• This means that the research we refer to is applicable to the patients we see

• Effectiveness studies in ADHD: – NICE guidelines: none– MTA: after 3 years there is no residual effect of

treatment; 8 year follow up shows considerable impairment

– 30% persistence with stimulantsCharach 04; Miller 04; Bussing 05

Long term outcome MTA

Effectiveness Study: Objectives• Is new and expensive really better?• Propensity analyses: who gets better?• How many drugs and why? • Safety of low dose Ris, combination Rx• Risk/benefit ratio of treatment• Individualization of treatment with comorbidity• Persistence with Rx and durability of outcome • Broad based outcomes: HRQL; Functioning;

Life skills; School and Work• Psychiatric side effects

Effectiveness Outcomes StudyMethod

1. 200 clinic patients2. No exclusions other than language3. All treatments measured naturalistically4. All direct and indirect costs measured5. Insured vs. uninsured? 6. Includes patients refusing treatment7. To what extent does improvement in

symptoms actually mediate improvement in functioning, quality of life, adaptive skills

Types of economic evaluation• Cost-Effectiveness Analysis (CEA)

– Benefits not explicitly valued - natural units used e.g. Life Years Gained (LYG) or cases detected

• Cost-Utility Analysis (CUA)– Benefits valued – typically based on LYG weighted

by an index of Quality of Life – Quality Adjusted Life Years (QALYs)

• Cost-Benefit Analysis (CBA)– Benefits valued - based on monetary valuations of

health improvements and expressed in dollars

Jumping through hoops

Safety Cost-EffectivenessQualityEfficacy

Measures• Adaptive functioning assessment system – apart from

the Vineland this is the only normed measure• Child Health Illness Profile – quality of life exclusive of

ADHD symptoms• Resource Utilization Questionnaire• Strengths and Difficulties Questionnaire• SNAP• Treatment Satisfaction Questionnaire for Medication –

Parent version• Pediatric Sleep Questionnaire• Pediatric Adverse Event Rating Scale (PAERS

www.captn.org)

Early Results

• Children who discontinue medication do not return to the clinic unless asked to do so

• Even in the face of symptom remission, mean ABAS score for self directed activity and home living < 5th percentile

• There is considerable use of multiple medication and medication switch

• There are selective medication responders

Next Year

• ICER/QALY• Propensity analysis• Weight changes: Ris; Atx; Stim• Sleep: percentage of sleep disorders and

naturalistic outcome of melatonin use• Is symptom an accurate proxy for overall

effectiveness and developmental gains?

Health• Sleep: ADHD is associated with delay in DLMO in adults

and children, RLS and PLMS• Nutrition: 44 children: majority have low Zn, Fe, Cu –

minerals which are MLT and DA cofactors and low long chain fatty acids

• Cardiac: ?risk of cardiac abnormalities in the face of developmental anomalies, associated difficulties (asthma, OM), exercise and medication

• DCD: 25% of the clinic impaired by clumsiness• Written Output: 75% of ADHD children dysgraphia• Medical Comorbidities: enuresis, asthma, otitis media• ADHD complicates PKU, neurofibromatosis, diabetes,

cystic fibrosis, congenital heart conditions

A. L. Colter, C. Cutler, and K. A. Meckling. Nutr J 7 (1):8, 2008.

Personalizing Treatment

Effect Size, What is?• The clinical relevance of the clinical trials, is analyzed

by Effect Size found, and is not related with the statistical significance.

• It’s used to understand the difference between the active drug and control.

• Represents an estimation related to a given scale in a given clinical trial

• Cohen’s recommendations are used to interpret the Effect Size1.

Effect size is not a measure of clinical significance. It is a measure of the size of the statistical difference between two conditions of points in time, and highly sensitive to accuracy of the measure used.

1Cohen J. Statistical power analyses for the behavioral sciences. 2nd ed. Mahwah, NJ: Lawrence, Erlbaum and Associates; 1988.

Time Of ImpairmentTime Of ImpairmentBiphentinBiphentin®® vs. vs. ConcertaConcerta®®

Concentration Time ProfileConcentration Time Profile

0

1

2

3

4

5

0 4 8 12 16 20 24

Time (h)

Met

hylp

heni

date

Pla

sma

Con

cent

ratio

n (n

g/m

L) MLR methylphenidate (20 mg) OROS methylphenidate (18 mg)

Unique Drug Response: Stim vs. Non Stim

• OROS MPH vs. Atx Newcorn Am J Psychiatry Jun 08

• N = 222 6 – 18 yo; cross over at 6 weeks• Anxiety, previous stim reaction, tics excluded• 43% of 70 patients who were stim non

responders responded to atx and of the 69 patients who did not respond to atx 42% responded to atx. 22% had no response to either

• MPH superior ES .2 for the group as a whole• No significant different in treatment naïve

population

Impact of comorbidity on Rx Selection

1. Time of drug must match time of impairment (i.e. Concerta a poor drug for early morning impairment)

2. Anxiety, tics, initial insomnia and possible concurrent SUD are relative indications for atomoxetine

3. Comorbid MDD requires treatment first4. Comorbid ODD and CD require concurrent

psychological management5. Explosive rage; emotional dysregulation, severe

irritability benefit from low dose SGAs6. Amphetamine as a group are more depressogenic

MPH and AMPH Side EffectsMPH and AMPH Side Effects

0.0

1.0

2.0

3.0

4.0

5.0

Troublesleeping

Poorappetite

Irritable Anxious-ness

Day-dreams

Bitingfingernails

Sadness Tics Headaches Night-mares

Mea

n se

verit

y

BaselineDextroamphetamineMethylphenidate

*,†

*

* *

*

*

*

** *

*

* **

*,†

*,††

†

Many Many ““side effectsside effects”” are characteristics of ADHD and improve are characteristics of ADHD and improve with stimulant treatment with stimulant treatment

Efron et al. Pediatrics 1997;100:662-6

*P <0.01 vs. placebo, †P <0.01 vs. methylphenidate

www.caddra.ca

Canadian ADD Resource Alliance1.Guidelines2.Treatment forms and scales3.Differential Diagnosis4.When to refer5.Annual conference6.Training Program

CHEAP AND EFFECTIVE: Psychological Interventions

1. Daily report card2. Psychoeducation3. Catch the good4. Skills block5. Decrease written output6. Environmental restructuring7. Minimize and structure homework8. Allocate tasks that can be done easily and well

School Based Interventions

1. Preferential seating2. Extra time on tests3. No homework4. Decreased demand for written output5. Peer buddies6. Daily report card 7. Keyboarding 8. Spare learning block at school

Treatment Implications• Externalize rewards• Chunk assignments• Use auxilliary aids such as agendas• Teach self regulation• Teach planning• Recognize that this is a disorder of performance

and not skill• Compensate for deficits in fluency with

increased time• Match environmental demands to skills• External scaffolding to provide attention

COGNITION

Executive Function Deficits• Response

disinhibition• Poor working memory• Problems sequencing• Blind to time• Blind to social

awareness• Inability to plan

• Problems with auditory processing

• Difficulty holding read material in mind

• Disorganization• Procrastination• Motivation

Working Memory

Helps the mind focus

“an attention controller”

Sluggish Cognitive Tempo or “ADD”

• Dreamy• Spacey• Sluggish – slow processing time• In their own world• Erratic performance and information

retrieval• Social Isolation• Distinct from ADHD-C and distinct from

ADHD-IA with residual hyperactivity

Inattentive Subgroups Are Impaired in Spatial WM Compared to Normal Controls

• Both Mild and Severely-Inattentive groups were significantly impaired on Spatial WM

• With word attack covaried, only Severely-Inattentive group was impaired on Spatial WM

02468

101214

Tota

l num

ber

corr

ect

Mild Severe NC

Spatial Span Spatial Manipulation

Wilk’s Lambda = .69, p = .02Tannock, Bedard 2005 - 2007

Effect of MPH dose on Verbal WM (Manipulation) Performance by Inattention Subgroup

0

0.51

1.5

22.5

3

Placebo Low Medium HighMPH Dose

Num

ber C

orre

ct

Mild Inattention (35) Severe Inattention (64)MPH Dose X Task x ADHD Subgroup Interaction Significant (F(3,288) = 2.69, p < .05)

Note: Schweitzer et al., 2001:

TO TAKE HOME• When its easy its very easy. • ADHD is mainly comorbid, severely impairing

developmental condition requiring careful assessment and follow up

• We don’t know who responds to what• Comorbidity impacts treatment outcome• In treating children we need to target their

overall health and well being as well as the disorder

• Treatment needs to be individualized to obtain remission in effectiveness outcomes