stimulant and non stimulant drug therapy and behavioral therapy in attention deficit hyperactivity disorder ,

1. Prof. Heba Essawy
Professor of Psychiatry
Ain Shams University
RECENT ADVANCES IN THE
PHARMACOTHERAPY OF ADHD

2. Roadmap
 MTS Study
 Psycho stimulants therapy in ADHD
 Non – stimulants in treatment of ADHD
 Impact of ADHD treatment and comorbidity
 Alterative treatment approaches in treating
ADHD

3. ADHD: Components of Treatment
 Medical Interventions
 Behavioral Interventions
 Psychosocial Interventions
 Education

4. ADHD: Treatment Planning
Goals
 Reduce major symptoms of ADHD
 Improve functioning in areas of impairment
Plan
 Address individual target symptoms
 Reassess and modify as necessary
Conners CK;*Jett JL. Attention Deficit Hyperactivity Disorder in Adults and children; The Latest
Assessment and Treatment Strategies; 1999.
Dulcan M. J Am Acad Child Adolesc Psychiatry. 1997;36 (10 suppl):85S-121S.

5. ADHD: MTA Study
NIMH and US Department of Education
 14-month, multicentre, randomized,
controlled trial
 579 children, ages 7-9 years, ADHD combined
type
 Medication management utilized dosing
strategies for all-day coverage
MTA Cooperative Group. Arch Gen Psychiatry. 1999;56(12):1073-1086.

6. Rationale for Multimodal
Interventions
 Medical and psychosocial interventions have
dose effects; outcomes differ among children
 Multimodal therapy address comorbid
conditions or target symptoms not
sufficiently improved by medication or
behavioural treatment alone
 Potential to improve outcomes in patients
Richters JE et al. J Am Acad child Adolesc Psychiatry. 1995;34(8):987-1000
Pelham WE Jr et al. J Clin Child Psychol. 1998;27(2):190-205.

7. ADHD: MTA Treatment Arms
1-Medication management only
 MPH tid, adjusted for best dose, other drugs if necessary; algorithmic
dose adjustments;
2- Intensive behavioural treatment only
 Parent training; structured teacher consultation; 8-week, full-time,
summer treatment program; 12 weeks of half-time, classroom,
behavioural specialist; case management by therapist/consultant
3-Medication management + behavioural treatment (combined)
4- Community-based care
 After assessment by investigators, parents could seek community
care (roughly 2/3 received medication
MTA Cooperative Group. Arch Gen Psychiatry. 1999;56(12):1073-1086.

8. ADHD: MTA Results
All treatments led to improvement in core ADHD
symptoms
Medication
management alone
Medication management
behavioural treatment
Nearly equal effectiveness
and superior to both:
Behavioural treatment alone
Community-based treatment
MTA Cooperative Group. Arch Gen Psychiatry. 1999;56(12):1073-1086.

9. Intensive Behavioural Treatment
in the MTA Study
 The intensive behavioural modification in the
MTA Study is unrealistic in day-to-day life:
 Parents received extensive training .
 Children participate in an 8-week, 40-hour-perweek treatment program and received one-on-
one help with classroom behaviour from an aide.
 Parents, teachers, and therapists were required
to maintain the highest possible degree of
communication.

10. MTA Study Conclusions
 Medication alone and combination regimens
were the most effective at reducing core ADHD
symptoms.
 Behavioural therapy alone was not effective at
reducing core ADHD symptoms, but did help to
promote positive interactions with others and
alleviate non-ADHD symptoms such as
aggressive behaviour, anxiety, and depression
Conners CK;*Jett JL. Attention Deficit Hyperactivity Disorder in Adults and children; The
Latest Assessment and Treatment Strategies; 1999

11. ADHD Treatment : Stimulants
 Stimulant medications are the
 Most studied
 Most commonly used
 Most effective
 First-line agents for treatment
Dulcan M. J Am Acad Child Adolesc Psychiatry; 1997; 36 (10 suppl.):85S-121S
Spencer T, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(4):409-432.

12. 
ADHD Treatment : Stimulants
(cont.)
Stimulant drugs effective in all age groups
 Vast majority of controlled studies in school-age boys (6-12
years old)
School-age
Adolescents
Adults
Preschool
Studies of stimulants for ADHD by Age Group
Spencer T et al. J Am Acad Child Adolesc Psychiatry. 1996; 35(4):409-432

13. ADHD: Stimulants Found to
Improve
Core symptoms
And
Inattention
Executive function
Impulsivity
Impulsive aggression
Hyperactivity
Social interactions
Academic productivity and
accuracy
Swanson JM, et al. Except Child. 1993;60:165-162.

14. ADHD: Stimulants (cont.)
 Methylphenidate (Ritalin®; Methylin®;
Metadate®; Concerta®; Daytrana (patch).
 Amphetamine mixed salts (AdderaI|®)
Contain d- and l amphetamine sulfate.
 Dextroamphetamine(Dexedrine®,
DextroStat®)
 Pemoline(Cylerl®) ( liver toxicity )

15. ADHD: Response to Stimulants
Meta-Analysis of Within-Subject Comparative Trails
Evaluating Response to Stimulant Medications
45%
40%
35%
30%
25%
20%
15%
10%
5%
0%
41%
28%
16%
AMP
MPH
Equal response to
Either Stimulant
AMP: Amphetamine (AdderaI|®, Dexedrine®; DextroStat®)
MPH: Methylphenidate (Ritalin®; Others)
Arnold LE. J Am Disord. 2000; 3(4):200

16. ADHD: Stimulant Dosing
 Medication should be given 7 days/week during
initiation of therapy and through titration to
optimal effect
 Coverage throughout the day is a goal
 This strategy allows
 Parents of children receiving medication to see
medication effects and benefits in off-school hours
 Better assessment of efficacy and side effects

17. ADHD: Pediatric Stimulant
Dosing
Medication
Starting Dose
Titration Rate
5 mg qd or 5mg
bid
5-10 mg every 3-5
days
Usual Dosing
Interval (Hours)
3 to 4 usually bidtid
Dexedrir®
DextroStat®
(dextroamphetamine)
(short-acting)
2.5-5 mg qd
2.5-5 mg every 3-5
days
4 to 6 usually bidtid
Adderall®
(mixed amphetamine
salts)
2.5-5 mg qd
2.5-5 mg every 3-5
days
4 to 6 usually qdbid
37.5 mg q AM
18.75 mg/week
qd
Ritalin®
(methylphenidate) (shortacting)
Cylert®
(pemoline)
Findling RL., Dogin JW. J Clin Psychiatry. 1998;59(suppl 7):42-49.
Ella J, et al. N Engl J Med. 1999;340(10):780-788.
Cyr M, Brown CS. Drugs. 1998;56(2):2 5-223.

18. The Impetus for Once-Daily
Dosage Options
 Need for medication coverage tor
 After-school extracurricular activities
 Social interactions
 Homework hours
 Problems with in-school dosing
- Privacy issues
- Ridicule by peers; decreased self-esteem

19. ADHD: New Delivery Systems
Newer once-daily dosage forms
 Concerta® (OROS® methylphenidate) FDA
approved, August 2000
 Metadate CD@ (extended-release
methylphenidate) FDA approved, April 2001
 Adderall XRTM (extended-release amphetamine
salts)
 Daytrana TM (transdermal methylphenidate)

20. OROS® Methylphenidate Analogue
Classroom Study
 Single-site, double-blind, crossover:
placebo, MPH tid, and OROS MPH
 All participants known MPH responders
 OROS MPH and IR MPH doses based on total
daily MPH dose for each individual
 5 mg MPH tid → 18 mg OROS qd
 10 mg MPH tid → 36 mg OROS qd
 15 mg MPH tid -—> 54 mg OROS qd
 68 subjects, ages 6-12 years,

21. OROS® Methylphenidate:
SKAMP Attention Ratings
Pellham WE Jr. Presented at: APA 2000 Annual Meeting; May 13-18, 2000; Chicago, IL

22. OROS® Methylphenidate:
Academic Productivity
Pellham . Presented at the AM Psychiatric Assoc. Annual Meeting; May 17, 2000

23. Extended-Release
Methylphenidate Capsules
(Metadate CD®)
 MPH 20 mg capsules use 2 beads
 IR beads comprise 30% of dose (6 mg)
 ER beads comprise 70% of dose (14 mg) for continuous
release of drug
 Approximately 8-hour duration of action
 1 multisite, placebo-controlled, doubleblind, clinical trial
 Doses individually titrated
 CGIS-T morning and afternoon ratings showed
significant improvement compared to placebo
(P<.001)

24. SLI381: Extended-Release
Amphetamine Salts (Adderall XRTM)
Pulse-Delivery System
Drug Layer
Overcoating
Drug Layer
Overcoating
Release-Delaying
Polymer
Bead
Overcoating
50%
50%
SLI381 Capsule

25. SLI381 (Adderall XRTM):
Academic Productivity
Number of Math Problems Completed Correctly
McCracken JT, et al. Presented at: AACAP Annual Meeting; Oct 24-29, 2000; New York.

26. Stimulant Adverse Effects (AE)
 Adverse effects are similar for all stimulants
 Decreased appetite
 Insomnia
 Headache
 Stomachache
 Irritability/rebound phenomena
NB: Rates of these adverse events may be high
prior to any medical intervention so baseline
levels should always be obtained

27. ADHD: AE Management Strategies
 Decreased appetite
 Monitor weight
 Administer with or after meals
 Give high-calorie snacks
 Initiate bedtime snacking
 Consider drug holidays

28. ADHD: AE Management Strategies
(cont.)
 Insomnia
- May be related to ADHD itself, a comorbid
disorder, or treatment
 Sleep hygiene/relaxation training
 Avoid evening dosing of stimulant
 Administer dose earlier in the day
 Try longer-acting preparation

29. ADHD: AE Management Strategies
(cont.)
 Headache/stomachache
 Decrease dose
 Switch to another stimulant
 Switch to second-line agent

30. ADHD: AE Management Strategies
(cont.)
 Irritability/moodiness; rebound effects
 Assess time occurring
 Shortly after dosing: may need to decrease dose
 Between doses (wearing off of medication): may be rebound
phenomena
 Adjust dosage
 Try longer-acting preparation
 Assess for other disorders

31. ADHD: Other Issues with
Stimulants
Growth suppression
 Weight: some studies show modest mean
weight deficits in ADHD children; other
studies show none
 Research suggests that stimulant treatment
may result in small effects in growth in
weight in some children
 Limited clinical concern
 Offset by adjustments in medication
administration and food supplementation
Spencer TJ, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1460-1469.

32. ADHD: Other Issues with
Stimulants (cont.)
Growth suppression
 Height: some studies have reported deficits in
growth in height in children (height deficits of 13 cm) whereas others have not
 Deficits found in prepubertal children but not in
adolescents
 Reports of increased growth during drug holidays
may reflect spontaneous normalisation - of height
gain
 Catch-up gains in height even with continued
stimulant treatment
Spencer TJ, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(11):1460-1469.

33. ADHD: Other Issues with
Stimulants (cont.)
Induction or exacerbation of tics
 Tics are usually transient; rarely patients develop
a chronic tic disorder
 When tics occur or increase
 Decrease dose
 Switch to another stimulant
 Adjunct agent to treat tics
 Try non stimulant medication

34. ADHD: Other Issues with
Stimulants (cont.)
 Pharmacotherapy and substance abuse
 Fear: stimulant therapy may lead to substance abuse
 Fact: untreated ADHD is a significant risk factor for
substance abuse in adolescence
 Pharmacotherapy for ADHD may have protective
effects

35. ADHD:
Pharmacotherapy and Substance Abuse
35%
Overall Rate of PSUD
P<.001
30%
% of Group
25%
20%
15%
33%
10%
13%
5%
10%
0%
unmedicated ADHD
(n=19)
Biederman J, et al. Pediatrics. 1999; 104(2):20.
Medicated ADHD
(n=56)
Control (n=137)

36. Nonstimulant Medications in
ADHD:
Sales
TCAs (n=33)
MAOIs (n=4)
SSRIS (n=1)
Venlafaxine (n=5)
Alpha-adrenergic
agents (n=7)
Neuroleptics (n=12)

37. ADHD: Tricyclic
Antidepressants
Advantages
Disadvantages
Established efficacy in
ADHD
Long duration of action
Efficacy <stimulants
Potential benefits on mood
and anxiety
Need for cardiac
monitoring
May be useful in patients
with tic disorders
Positive effects on sleep
Biederman J. J Clin Psychiatry. 1998;59(suppl 7):4-16.
Serious potential cardiac
effects in children

38. ADHD: Bupropion
(Wellbutrin®)
Advantages
Disadvantages
Efficacy in ADHD
Few studies in ADHD
Adequate duration of action
(bid dosing)
Limited effect size
May decrease hyperactivity
and aggression
May
decrease
threshold
May improve cognitive
performance
May exacerbate tics
Smoking cessation
Conners CK, at al. J Am Acad Child Adolesc Psychiatry. 1996;35(10)=1314-1321.
Biederman J. J Clin Psychiatry. 1998;59(suppl 7) :4-16.
seizure

39. ADHD: Clonidine (Catapres®)
Advantages
Disadvantages
Activity in aggressivity and
agitation
Clinical effects may take
several weeks
Improves ability to fall asleep
Does not affect inattention
symptoms
Sedation, disrupted REM sleep
Risk of adverse
cardiovascular
effects, depression, and
decreased glucose tolerance

40. ADHD: Guanfacine (Tenex®)
Advantages
Disadvantages
Longer duration of action
than clonidine
Very limited efficacy and
safety data
Less sedation than
clonidine
Sedation

41. Pediatric Dosing Guidelines
Medication
Average Daily Dose
TCA antidepressants
Desipramine
Imipramine
Titrated up to 25-150 mg (1-5 mg/kg)
Nortriptyline
Titrated up to 10-75 mg (0.5-3 mglkg)
Other antidepressants
Bupropion
3.0-6.0 mg/kg*
Venlafaxine
2.0-5.0 mg/kg*
Alpha-adrenergic agents
Clonidine
0.1-0.3 mg*
Guanfacine
0.5-3.0 mg*
*Given In divided doses.
Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 1999;38(6):614-619. Spencer T, et al. 1998.
Conner DF, et al. J Child Adolesc Psychopharmacol. 1998;8(l):27-38.

42. Atomoxetine Receptor Activity
 Potent selective inhibitor of norepinephrine
reuptake
 Increase extracellular NE but produces an
indirect increase in dopamine in prefrontal
cortex

43. Strattera® (atomoxetine HCl)
Mechanism of Action
Tyrosine
Tyrosine
Dopamine
Dopamine
Norepinephrine (NE)
NE
Presynaptic Neuron
NE
NE
NE
NE
NE Transporter
Atomoxetine
Synaptic Cleft
NE
NE Receptor
NE Receptor
Postsynaptic Neuron
Simpson D, et al. Drugs. 2004;64(2):205-222.
Lilly confidential. Do not copy. Copyright © 2013 Eli Lilly and Company.
43

44. A Fixed-Dose Study of Atomoxetine and
Placebo in Children and Adolescents
Atomoxetine 1.8 mg/kg/d
Atomoxetine 1.2 mg/Kg/d
n=84
Atomoxetine 0.5 mg/kg/d
n=44
Placebo
Washout
and
Evaluatio
n
n=85 -
n=84
8-Week Acute Therapy Period
Extension
(ongoing)

45. ADHD RS Total Score
Improvement
Atomoxetine Efficacy in placebo- controlled
pediatric studies aaaa
* *
***
***
***
***
*
a
*p<.05
***p≤.001
aIn Study III, 1.2
mg/kg/day is fixed dose, while in all other studies this dose represents a titrated dose
1.
Spencer et al. J Clin Psychiatry 2002;63(12):1140-47.
2.
Michelson et al. Pediatrics 2001;108(5):e83.
3.
Michelson et al. Am J Psychiatry 2002;159(11):1896-901.
4.
5.
Weiss et al. J Am Acad Child Adolesc Psychiatry 2005;44(7):64755.
Kelsey et al. Pediatrics 2004;114(1):e1-8.

46. Child Health Questionnaire
*Pairwise test vs placebo R-05. **Pairwise test vs placebo P<001.
Test for linear dose response P<.05.

47. Tolerability of Atomoxetine in Children
(All Placebo-Controlled Studies)
Atomoxetine
(N=425)
Placebo
(N=292)
P-value
Appetite decreased
60(14.1%)
17(5.8%.)
<.001
Dizziness
26(6.1%)
7(2.4%)
.019
Dermatitis
19(4.5%)
5(1.7%)
.056
Dyspepsia
19(4.5%)
4(1.4%)
.029
Unexpected benefit
13(3.1%)
3(1.0%)
.077
Constipation
10(2.4%)
3(1.0%)
.259
Mood swings
10(2.4%)
2(0.7%)
.136
Influenza
9(2.1%)
3(1.0%)
.377
Events reported by at least 2% of atomoxetine patients and at least two times more
common than placebo.

48. ADHD: Childhood
Common Comorbid Diagnoses
Biederman J, et al. J Am Acad Child Adolesc Psychiatry. 1996;35(3):343-351.
Pllszka SR. J Clin Psychiatry. 1998;59(surppl 1,50-58.
Biederman J, at al. J Am Acad Child Adolesc Psychiatry. 1999;38(8):966-975.
Spencer T, et al. Pediatr Clin North Am. 1999;46(5):915-927.

49. TREATMENT IMPACT OF
CD
 Stimulant medication or ATX effective and
decrease
- Physical aggression
-Verbal aggression
-Negative social interactions
- Covert antisocial behaviour
 Antihypertensive , atypical AP for highly aggressive
, explosive cases
 Mood stabilizers are unhelpful
 Behavioural management techniques are
employed
Spencer T, et al Pediatr Clin North Am. 1999;46(5):915-927.

50. Treatment Impact of anxiety




Prioritize treatment
Reduced response to stimulants
Stimulants make anxiety worse ?
Stimulants make some cognitive abilities worse
in combined cases
 ATX and GUANFACINE xr do not worsen anxiety
in comorbid cases
 SSRI may be effective for anxiety disorders

consider buspirone, high-potency benzodiazepines
for anxiety
Spencer T, et al. Pediatr Clin North Am. 1999;46(5):915-927.
Conners CK J Attn Disord. 2001;4(suppl 1):30.

51. Treatment Impact of anxiety
 Probe more for physical or sexual abuse or
bulling at school
 More responsive to behavioral therapy ( MTA)
 Better response to social skill training

52. Treatment impact of
Depression
 Highly prevelant from 20 to 45%
 Severe explosive anger may be a sign of
either childhood severe mood dysregulation
(SMD) or Bipolar disorder

53. Treatment impact of Depression
 Combination therapy often required
 Stimulants effective in treating ADHD but not
mood
 SSRIs may be effective in treating depression
but not ADHD
 Noradrenergic agents ATX may treat both
 Antihypertensive , Atyipical AP and Mood
stabilizer are useful.
Spencer T, et al. Pediatr Clin North Am. 1999;46(5):915-927.

54. ADHD: Comorbid Depression (cont.)
ADHD treatment
 Noradrenergic
antidepressants
 Stimulants
Depression
treatment
 SSRIs
 Bupropion
 Venlafaxine

55. Treatment Impact Of Bipolar
Disorder
 Juvenile mania is highly comorbid and
frequently mixed with depressive
features, ADHD, anxiety, and ODD/CD
 Prioritize treatment
 First treat mania or psychosis
 Mood stabilizers
 Atypical neuroleptic
 ADHD

56. Impact of Treatment of
Tics/Tourette's
Tics develop in 1-2% of ADHD receiving high dose
of Amphetamine but not Methylphenidate
 Stimulant medication is not contraindicated
 If unable to tolerate stimulants consider
alternative ADHD medication (Atx or TCA)
 Adjunctive agents for tic control can be
successfully combined with stimulants (alpha
agonist, risperidone, pimozide)

57. Treatment Impact Of
ASD
 20- 25% of ADHD have ASD.
 20- 5-% of ASD have ADHD.
 ADHD medication can be used to treat ADHD
symptoms effectively in context of ASD

58. Treatment Impact of ODD
 Both stimulants and ATX reduce ODD with
ADHD but not ODD alone.
 Requires adjunctive parents training in
behavior management .
 Response is aged related , 60-75% successful
for children
 25-35% treatment response after 13 ys of age
.

59. TREATMENT OF IMPACT OF learning
Disorders
 Hand writing problem (60%)
 Comprehension defect
 Comorbid reading , spelling and math
disorder do not improve from stimulants
 Reading ability improve on ATX

60. TREATMENT OF IMPACT OF learning
Disorders
 Comorbid hand writing and comprehension
defect are likely to improve from stimulants if
secondary to ADHD itself

61. ADHD: Alternative Therapies
Effective in ADHD children :
 Fish oil
 Lithium
 Zinc
Arnold LE. J Affn Disord. 1999;3(l):30.

62. ADHD: Alternative Therapies
Limited data
EPA
Ineffective or dangerous
Megavitamin therapy
Flax seed oil
Megamineral therapy
Ginko preparation
Caffeine
EEG biofeedback
Primrose oil
L- carnitine
DHA
Mg- VIT B6- VIT C
Arnold LE. J Attn Disord. 1999;3(1):30.

63. Summary: Treatment of ADHD
 In treatment planning targeting major areas of
impairment and comorbidities .
 Treatment may employ balance of behavioral and
medical intervention
 Stimulant medications are the gold standard for
medical intervention if no comorbidity is associated
 Apply Low- Slow- GO approach to titrating doses

64. GOLDEN RULES IN TREATMENT OF
ADHD
 ATTAIN
 ATCHIVE
 ASSESS
 ADHERE