1. The Basics of Clinical Psychopharmacology: Pediatric Psychopharmacology
Edition 2, Lecture 5
ASCP Model Curriculum
for
Medical Students

2. Vishal Madaan, MD* Christopher J. Kratochvil, MD**
Authors
Vishal Madaan, MD*
Christopher J. Kratochvil, MD**
*University of Virginia Health System
**University of Nebraska Medical Center

3. Objectives from ADMSEP Psychiatry Learning Objectives Taskforce, 2007
By completion of the clerkship/medical school, the student will be able to:
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4. ADMSEP Objectives—con’t
1. Discuss the common, currently available psychotropic medications with regard to clinical indications and contraindications, presumed mechanism of action and relevant pharmacodynamics, common and serious adverse effects, pharmacokinetics, evidence for efficacy, cost, risk of drug-drug interactions and drug-disease interactions, and issues relevant to use in special populations (e.g., pregnancy and lactation, childhood and adolescence, the elderly, persons using herbal and over-the-counter treatments).
2. Propose selected psychotropic pharmacotherapy for designated patients and provide clinical reasoning that includes discussion of factors influencing treatment selection (e.g.,patient-specific and drug-specific variables, scientific evidence).
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5. ADMSEP Objectives—con’t
3. Discuss the factors relevant to implementing, monitoring and discontinuing psychotropic pharmacotherapy including drug dosing, treatment duration, and adherence, and make management recommendations for dealing with an unsuccessful treatment trial (e.g., lack of efficacy, intolerability).
4. Counsel patients about psychotropic pharmacotherapy including risks and benefits of recommended treatment, treatment alternatives, and no treatment
5. Identify and discuss resources to maintain an up-to-date knowledge of psychotropic pharmacotherapy
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6. ADMSEP Objectives—con’t
6. Discuss special issues and concerns related to specific psychotropic drug classes including metabolic, hematologic, hepatic, etc.
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7. Objectives for MS II At the end of this lecture, the student will:
Be able to articulate the basics of using psychotropics in children and adolescents
Be able to name the basic drugs used for children and adolescents and their clinical indications

8. Objectives for MS III At the end of this lecture, the student will:
Be able to list appropriate dose ranges for at least 3 drugs used for children and adolescents
Be able to elucidate the major side effects seen in the use of the various drugs

9. Outline Children are not small adults! Epidemiology
3 topics discussed:
ADHD
Childhood Depression
Anxiety Disorders
Questions

10. Children are not small adults!
Young children may not be able to describe their internal states
Developmentally relevant vocabulary must be developed for working with children and families
Physiologically different
Start low, go slow, but higher doses may be tolerated and required, on a mg/kg basis

11. Epidemiology of Common Child and Adolescent Psychiatric Disorders
ADHD: Prevalence
ADHD is one of the most common mental disorders in childhood
Conservative estimates of 4-7% in grade school children
4.4 million, 7.8%, of 4-17 y.o. U.S. children have a history of ADHD by parent report (CDC, MMWR Weekly 54: , 2005)

12. Pediatric Depression Epidemiology Distribution by Sex
0.3% of pre-schoolers
2% of school-aged children
5% of adolescents
20-25% lifetime prevalence by the end of adolescence (Kessler et al, Biological Psychiatry 2001;49: )
Distribution by Sex
Approximately equal before puberty
2:1 female to male ratio after puberty

13. Child & Adolescent Anxiety Disorders
Among the most prevalent of child and adolescent psychiatric disorders
15.4% children in pediatric primary care sample of y.o. met criteria for an anxiety disorder during a 1-year period (Benjamin et al 1990)
Of 792 eleven-year-olds, 3.5% separation anxiety d/o, 2.4% simple phobia, 2.9% overanxious d/o, 1% social phobia (Anderson et al 1987)

14. Autism Spectrum Disorders
Autistic Disorder
Occurs in 4 out of 10,000 children
Distributed equally among all socioeconomic levels
Male to Female ratio 3:1 (Females affected more severely, with greater neurological impairment)
Asperger’s Syndrome
More common in boys than girls 10:1
Not associated with socioeconomic status or parental education
Prevalence was thought to be per 10,000
A Swedish survey estimated per 10,000

15. Attention-Deficit/Hyperactivity Disorder

16. All treatment arms found to be effective on an absolute basis
ADHD: MTA Results
All treatment arms found to be effective on an absolute basis
Nearly equally effective and superior to both:
Medication management alone
Medication management + behavioral treatment
Behavioral treatment alone
Community based treatment
(MTA Study Group, Arch Gen Psych, 1999)

17. Clinical Use of Stimulants
Safety and efficacy data beginning in the 1930’s, with their role in treating children well established by the 1970’s.
One of the best studied treatments in pediatric psychopharmacology
One of the most robust responses in pediatric psychopharmacology

18. Pharmacotherapy of ADHD
Psychostimulants
Methylphenidate (approved for > 6yrs)
Methylphenidate (in various formulations)
Dexmethylphenidate
Amphetamine (approved for > 3yrs)
Dextroamphetamine
Mixed Amphetamine salts
Lisdexamfetamine

19. Pharmacotherapy cont’d
Non-stimulant Agents (Atomoxetine, Guanfacine XR and Clonidine XR are FDA approved for ADHD)
Atomoxetine (approved for 6yrs and up)
Bupropion
Desipramine
Clonidine (IR and XR)
Guanfacine (IR and XR)

20. Drug release technology: “biphasic” release profile with
Time Release Capsules
Protective membrane
20 mg
Protective
membrane
Release control
MPH
Core
ER beads
IR beads
Drug release technology: “biphasic” release profile with
combination of intermediate release (IR) and extended release (ER) MPH beads

21. Oros® Technology During operation Before operation Water
Orifice/exit port
Drug compartment #1
Drug compartment #2
Push compartment
Drug overcoat
Rate- controlled membrane
Before operation

22. Longer Acting Treatment Options:Stimulants
Methylphenidate
Metadate CD®: Biphasic (30% immediate, 70% 3 hours later)
Ritalin LA®: Biphasic (50% immediate, 50% 4 hours later)
Focalin® XR: Biphasic (50% immediate, 50% 4 hours later)
Concerta®: Triphasic (overcoat of immediate release & osmotic pump)
Daytrana® patch: Transdermal patch applied to hip
Quillivant XR TM: Extended release oral suspension
Amphetamine
Extended release d,l-amphetamine (Adderall XR™): biphasic (50% immediate, 50% 4 hours later)
Lisdexamfetamine (Vyvanse)

23. Optimizing Response to Stimulants
IR = 4 hrs Ritalin LA = 8 hrs
Metadate CD = 6-8 hrs Concerta/Adderall XR = hrs
In general, use extended-release formulations
Give first dose as early as possible in AM
Increase dose to ensure maximum benefit achieved
Sculpt the dose: examples of potential combinations
Give immediate release TID
Give Metadate CD or Ritalin LA BID
Give IR early AM and Concerta/Adderall XR around noon
Give Concerta/Adderall XR early and IR around 6 PM
Greenhill LL, Pliszka S, Dulcan MK, et al; American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41(suppl 2):26S-49S.
Silver L. Update on ADHD medications. LD Online [serial online]. Available at: Accessed October 16, 2003.
Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry 2002;41(suppl 2):26S-49S

24. Adverse Effects of Stimulants
Appetite suppression
Insomnia
Tics
Growth suppression
Cardiovascular
Rare: psychotic symptoms, mania, seizures

25. Atomoxetine (Strattera™)
Selective noradrenergic reuptake inhibitor
FDA approved for age 6 and up in November, 2002
Dosed by body weight, titrated based on tolerability and response
Initiated at approximately 0.5mg/kg/day and gradually titrated to target dose (1.2 mg/kg/day) to improve tolerability
FDA approved maximum 1.4mg/kg/day
Delayed onset of action

26. Indications for Atomoxetine
FDA approved for the treatment of children 6 years of age and older, adolescents, and adults
Low substance abuse liability, so often seen as an option where there is a high risk of substance abuse or diversion
May be useful for those with comorbid anxiety or comorbid Tourette’s

27. Adverse Effects of Atomoxetine & Management
Dyspepsia
Sedation
Irritability
Hepatic
Suicidality

28. Preschoolers with ADHD Treatment Study (PATS)
Aim- To test the efficacy and tolerability of methylphenidate for preschool children
N= 165
3-5 years old
12 weeks
Randomized, placebo-controlled. Cross-over with 4 fixed doses plus PBO (1 week each), followed by a 4-week parallel group, and a 10-month naturalistic maintenance phase.
Greenhill, Kollins, Abikoff et al, J Am Acad Child Adolesc Psychiatry, 2006, 45(11):

29. PATS <10% responded to parent training alone
Significant improvements noted with methylphenidate 2.5mg TID, 5mg TID, and 7.5mg TID. Mean optimal dose 14.2 mg/d
Only 21% on best-dose MPH and 13% on PBO met remission criteria
Emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability were most frequently reported adverse effects
At 1 year mean gains in growth -1.38cm & -1.3 kg below expected

30. Depression

31. DSM-IV-TR Diagnostic Criteria
Five or more symptoms present for 2 weeks (every day or nearly every day)
At least one symptom is depressed/irritable mood or anhedonia
Symptoms not due to general medical conditions or substances
Significant distress or impairment in functioning

32. DSM-IV-TR Diagnostic Criteria
Depressed mood- or irritability in children/adolescents
Sleep- increased sleep or insomnia
Interest- markedly diminished interest/pleasure
Guilt- feeling worthless or inappropriate guilt
Energy- fatigue or loss of energy
Concentration- diminished ability to think/concentrate
Appetite- sig. wt. loss or gain (e.g.. 5%), diminished appetite, in kids failure to make expected gains
Psychomotor- physically slowed or agitated
Suicide- thoughts, attempts, or recurrent thoughts of death

33. Clinical Presentation
Young children
Physical Complaints
Depressed or Irritable Mood
Withdrawn & Sad Appearance
Adolescents
Grouchy & Sulky commonly
Restless
Withdrawn
Physically Slowed
Lack of enjoyment in activities

34. Pediatric Depression
Fluoxetine and Escitalopram are the only antidepressants FDA approved for the treatment of depression in children or adolescents

35. Treatment Strategies
TADS: Treatment of Adolescents with Depression Study
Examined effectiveness of fluoxetine, CBT, combination, and placebo
NIMH sponsored; 12 sites nationally
Stage I: Acute treatment for 12 weeks
Stage II: Consolidation for 6 weeks
Stage III: Maintenance for 18 weeks
Stage IV: One year open follow-up

36. TADS Treatment Response with acute treatment:
Combination: 71%; Fluoxetine: 61%
CBT: 43%; Placebo: 35%
Conclusions:
Combination of fluoxetine & CBT is most effective.
Fluoxetine alone is effective, but not as effective as combination

37. Suicidality and Antidepressants
Meta-analysis from 24 antidepressant studies conducted in pediatric patients (Hammad 2004)
4% had suicidal thoughts/behaviors on medication, 2% on placebo; no completed suicides
Black box warning for antidepressant use in children and adolescents

38. Suicidality and Antidepressants
20% decline in pediatric antidepressant use.
Olfson, 2003: Inverse relationship between regional change in antidepressant use and suicide rates (1% ↑ in antidepressant use associated with a ↓ of 0.23 suicides/100,000 adolescents/year.
CDC, Feb 2007: Child & adolescent suicide rate in 2004 rose for the first time in more that a decade (18%)

39. The Treatment of Resistant Depression in Adolescents Study (TORDIA)
Aim: to compare the effectiveness of an alternative antidepressants (SSRIs or venlafaxine), alone and in combination with CBT, in adolescents with depression who failed an adequate initial SSRI trial
12 weeks of
Switch to 2nd, different SSRI (paroxetine, citalopram, or fluoxetine)
Switch to a different SSRI + CBT
Switch to venlafaxine
Switch to venlafaxine + CBT
N= 326
12-18 years old
12 weeks of acute treatment followed by a 12 week continuation
Brent, Emslie, Clark et al, JAMA 2008, 299:

40. TORDIA
The combination of CBT and a switch to another antidepressant resulted in a higher rate of clinical response (54.8%) than did a medication switch alone (40.5%)
There was no difference in response rate between venlafaxine and a second SSRI, although venlafaxine was associated with an increase in diastolic blood pressure & pulse and more skin problems than SSRI

41. Pediatric Anxiety Disorders

42. Treatment Strategy for Anxiety Disorders
Clinical management of anxiety disorders requires 3 distinct areas of dysfunction be addressed
the primary symptoms: Hyperarousal, restlessness, anxiety, obsessions, compulsions
the anticipatory anxieties—may respond to psychotherapeutic interventions
behavioral disturbances in patient or environment as a result of the primary symptoms or anticipatory anxieties
Pharmacological interventions are clearly indicated, but often need to be combined with psychotherapeutic interventions

43. Child and Adolescent Anxiety Multimodal Study (CAMS)
Aim: to compare sertraline and CBT, alone and in combination, to PBO.
N=488 subjects with separation anxiety disorder, generalized anxiety disorder, or social phobia
Age: 7-17 years
Duration- 12-week trial
Walkup et al, NEJM, 359(26): : 2008

44. CAMS All 3 active treatments demonstrated efficacy
81% response to COMB, 61% CBT, 56% sertraline, 26% PBO
COMB > CBT=Sertraline > PBO

45. Research Units of Pediatric Psychopharmacology (RUPP) Fluvoxamine Study
Fluvoxamine (RUPP studies 2001, 2002) mg, 8 wks, n=128 in 6-17 yrs
Generalized Anxiety Disorder, Separation Anxiety Disorder, or Social Phobia persisting after 3 wks supportive psychotherapy
Response Rates= FLVX 76% v 29% placebo
Adverse effects= stomachache, motor activation 28% v 12% placebo

46. Research Units of Pediatric Psychopharmacology (RUPP) Fluvoxamine Study
6 mo open label extension-94% continued remission
Fluvox non-responders-> Fluoxetine (n=14) mg 71% response by clinician rating and PARS
Higher level of depression, SP and severity of illness- less drug efficacy;
ES=1.1 largely because of low placebo response
Take home message: If no response from first SSRI, try a second one

47. The Pediatric Obsessive-Compulsive Disorder Treatment Study (POTS)
Aim- to test efficacy of sertraline and CBT, alone and in combination in children with OCD, compared to PBO
OCD in Children and Adolescents: A Cognitive Behavioral Approach, JS March & K Mulle, Guilford Press
N= 112
7-17 years old
12 weeks
The Pediatric OCD Treatment Study (POTS) Team, JAMA (16): pp

48. Pediatric OCD Treatment Study (POTS)
Compared efficacy of 4 different treatment options: Sertraline alone, sertraline +CBT, CBT alone & placebo alone; n=112; 12 weeks
Randomized parallel groups
Entry criteria CYBOCS=16; Mean of 24.6 with only ADHD meds allowed
Sertraline- Upward titration from 25→200 mg/d over 6 weeks
Outcome measure of remission: CYBOCS <10

49. POTS: Outcome Mean daily dose of sertraline Effect sizes
With combined treatment:133 mg/day
Sertraline alone: 176 mg/day
Effect sizes
CBT: 0.97
Sertaline alone: 0.67
Combined treatment:1.4
Remission rates (CYBOCS=10) for combined 53.6%; CBT alone 39.3%; sertraline 21.4% and placebo 3.6%

50. POTS CBT alone, sertraline alone, COMB all superior to PBO
COMB was most effective, beat sertraline alone & CBT alone
CONCLUSION: children & adolescents with OCD should begin treatment with the combination of CBT plus an SSRI or CBT alone

51. FDA Atypical Antipsychotic Indications in Children and Adolescents
Bipolar Disorder
(10-17 yo)
Schizophrenia
(13-17 yo)
Irritability in Autism
Clozapine
Olanzapine
X (13-17 yo) X
Risperidone
X (5-16 yo)
Quetiapine
Ziprasidone
Aripiprazole
X (6-17 yo)

52. Discussion Questions Question 1
1. Which of the following antidepressants have been FDA approved for the treatment of major depressive disorder (MDD) in youth?
Fluoxetine
Sertraline
Fluvoxamine
Paroxetine
Citalopram

53. Question 2
2. Which of the following has been associated with the best outcomes in adolescents with depression?
Fluoxetine alone
CBT
Paroxetine + CBT
Fluoxetine + CBT

54. Question 3
3. Which non-stimulant is FDA approved for the treatment of ADHD?
Atomoxetine
Imipramine
Bupropion
Risperidone
Aripiprazole

55. Question 4
4. Which stimulant medication has the largest amount of data pertaining to safety & efficacy in preschool children?
Amphetamine
D-amphetamine
Atomoxetine
Methylphenidate
D-methylphenidate

56. Answers A D

57. End of Lecture