Pharmacology Children

Master Course 05

Update on Pediatric Psychopharmacology

Director(s): Christopher J. Kratochvil, M.D. Date: Tuesday, May 8, 2012 Time: 9am-4pm Location: 201 C, Level 2, Convention Center

American Psychiatric Association • Integrated Care • Philadelphia, May 5-9, 2012 • 165th Annual Meeting

Master Course 05

Educational Objectives: At the conclusion of this session, the participant should be able to: 1) Current

clinical guidelines for the use of pharmacotherapy in pediatric psychiatric disorders; 2) Practical clinical use of psychopharmacology and management of

adverse effects; and 3) Recent research on pharmacotherapy in common psychiatric disorders of childhood.

Course Information

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Master Course 05

Karen Wagner, M.D.

Christopher McDougle, M.D.

John Walkup, M.D.

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Agenda

Master Course: Update on Pediatric Psychopharmacology

9am-4pm

9:00-9:10 Welcome & Introductions Chris Kratochvil, M.D. 9:10-10:35 Pharmacotherapy for Children & Adolescents with ADHD

Chris Kratochvil, M.D. 10:35-12:00 Pharmacotherapy of Autism

Chris McDougle, M.D. 12:00-1:10 Lunch (on your own) 1:10-2:35 Treatment in Children with Anxiety Disorders John Walkup, M.D. 2:35-4:00 Update on Pharmacological Treatment for Pediatric Mood

Disorders Karen Dineen Wagner, M.D., Ph.D.



Outline

Master Course: Update on Pediatric Psychopharmacology

This course will provide participants with practical information on the use

of psychotropic medication in the treatment of children and adolescents in their practices. It will provide an overview of recent data in pediatric psychopharmacology across a broad group of psychiatric disorders. All four of the presenters are active clinicians and researchers in their areas of interest. They will discuss the role of pharmacotherapy in the treatment of these disorders, incorporating relevant aspects of recent clinical research. Current clinical guidelines and the management of adverse effects will be reviewed as well.

The four presentations and discussions will address:

· Dr. Kratochvil: Pharmacotherapy for children and adolescents with ADHD

o Principles on the use of psychotropic medications with children and adolescents

o Risk benefit assessment of psychopharmacology o Psychopharmacology in young children o Stimulant and non-stimulant pharmacotherapy for children

and adolescents with ADHD o Clinical management of pharmacotherapy for ADHD:

optimizing dosing and managing adverse effects · Dr. Walkup: Treatment of childhood anxiety disorders: the

evidence-base and beyond o Overview of anxiety disorders o Treatment of OCD o Treatment resistant OCD: including strategies for switching

medication and augmentation of pharmacotherapy o Treatment of generalized anxiety disorder, social phobia,

separation anxiety disorder o Child & Adolescent Anxiety Multimodal Study (CAMS)

· Dr. McDougle: Psychopharmacology of autism o Brief Overview of the autism spectrum disorders (PDD) o Identifying target symptoms for drug therapy in autism

spectrum disorders § Motor hyperactivity, inattention § Interfering repetitive behavior § Irritability (aggression, self-injury, severe tantrums) § Impaired social relatedness § Sleep disturbance

o Results from controlled drug studies in the treatment of autism spectrum disorders

o Potential adverse effects associated with drugs used in the treatment of autism spectrum disorders

· Dr. Wagner: Update on pharmacological treatment of pediatric mood disorders

o Recent controlled pharmacotherapy trials in the treatment of major depression in children and adolescents

o Role of cognitive behavioral therapy in the treatment of major depression and prevention of relapse

o Safety and tolerability of antidepressants o Pharmacotherapy for bipolar disorder in children and

adolescents o Safety, monitoring, and management of pharmacotherapy

for bipolar disorder o Psychosocial interventions for bipolar disorder in children

and adolescents



Slides

1

Pharmacotherapy for Children & Adolescents

with ADHDChristopher J. Kratochvil, M.D.Professor of Psychiatry & Pediatrics

Assistant Vice Chancellor for Clinical ResearchUniversity of Nebraska Medical Center

Omaha, Nebraska

2

Disclosures: Past 12 months

Consultant Consultant for Quintiles.DSMB for Pfizer & Seaside.

Publishing Oxford Press

Research funding Eli Lilly, Shire

3

Off-Label Medication Use

Several medications in this presentation are discussed in the context of off-label uses outside of the FDA-approved indication.– Age, diagnosis, dose

4

FDA-Approved Indications/Dosing

Off-label use of drugs represents 50-75 % of pediatric medication use (Zito, JCAP 2008)Product information is developed cooperatively by the pharmaceutical manufacturer and FDA, generally reflecting evidence from manufacturer sponsored studies.Does not necessarily reflect the evolving evidence base that may include NIH-funded or investigator-initiated studies.Thus, prescribers need to be aware of randomized controlled trials in the literature, consensus guidelines, practice parameters as well as product information.

Walkup, Practice Parameters on Use of Psychotropic Medications in Children & Adolescents, JAACAP, 2009

5

Principles on the Use of Psychotropic Medication in Children and Adolescents

(Walkup, Practice Parameter AACAP, JAACAP 2009)

Psychiatric evaluation prior to initiating pharmacotherapy.Medical history & medical evaluation (when appropriate), prior to initiating pharmacotherapy.Communicate with other professionals involved with the child to obtain collateral history and establish monitoring of treatment outcome and adverse effects.Develop a psychosocial/psychopharmacological treatment plan based on the best available evidence.Develop a short- and long-term monitoring plan.Be cautious when implementing a treatment plan that cannot be appropriately monitored.

6


(Walkup, JAACAP 2009)

Psychiatric evaluation prior to initiating pharmacotherapy.Medical history & medical evaluation (when appropriate), prior to initiating pharmacotherapy.Communicate with other professionals involved with the child to obtain collateral history and establish monitoring of treatment outcome and adverse effects.Develop a psychosocial/psychopharmacological treatment plan based on the best available evidence.Develop a short- and long-term monitoring plan.Be cautious when implementing a treatment plan that cannot be appropriately monitored.

7


(Walkup, JAACAP 2009)Information regarding the diagnostic assessment and education regarding the child’s disorder, treatment and monitoring plan is provided to the child & family.Assent of the child and consent of the parents completed before initiating medication and at important points during treatment.The assent and consent discussion addresses risks and benefits of the proposed and alternative treatments.Medication trials of adequate dose and adequate duration.Reassess the patient if no response to initial medication trial.Clear rationale is needed when using medication combinations.Clear and specific plan should guide discontinuation of medication.

8

Pharmacotherapy for the Preschool Child

9

Psychotropic Medications in Preschool Children with Medicaid: 1991-2001 (Zito, 2007)

10

Psychopharmacological Treatment for Very Young

Children: Contexts and Guidelines

Gleason MM, Egger HL, Emslie GJ et al., JAACAP, 2007; 46(12):1532-

1572

11

Psychopharmacological Tx Of Young Children

Assessment- a comprehensive, developmentally sensitive assessment is a necessity. – Multiple assessment visits, multiple informants,

and generally within the context of a multidisciplinary team

– Emotional and behavioral symptoms, relationships, medical history, developmental history/status, parental/environmental stressors/supports should be addressed.

– Parental psychopathology and treatment needs should be assessed as well

12

Psychopharmacological Tx Of Young Children

Nonpharmacological treatments should be considered first– The psychotherapeutic interventions evidence-

base for preschoolers is limited, but growing– Psychotherapeutic interventions should be tried

first, and continue concomitantly with medication if medications are introduced

13

Pharmacotherapy AlgorithmsAt every treatment initiation point reassess diagnosis and clinical formulationPsychotherapeutic treatments are an integral part of every algorithmA discontinuation trial should follow each successful psychopharmacological treatment Avoid medications when therapy is likely to produce good resultsA system should be developed to track symptoms & impairment

14

Psychopharmacological Treatment for Very Young Children: Contexts & Guidelines

ADHD Algorithm1. Comprehensive diagnostic assessment2. Behavioral intervention, min. 8 weeks3. Methylphenidate4. Amphetamine5. Alpha agonist or atomoxetine

Gleason et al, JAACAP December 2007

15

Pharmacotherapy (and other stuff) for Children &

Adolescents with ADHD

16

Common Questions asked by Patients and Parents

17

Why didn’t kids have ADHD when I was growing up?

18

ADHDHistorical Timeline

1950 1980

Minimal Brain Dysfunction

1968

Hyperkinetic Reaction of Childhood (DSM-II)

Minimal Brain Damage

1987 1994

Attention Deficit Hyperactivity Disorder (DSM-III-R)

Attention Deficit Disorder + or -Hyperactivity (DSM-III)

Attention Deficit/Hyperactivity Disorder (DSM-IV)Attention Deficit/Hyperactivity Disorder (DSM-IV)

1902 19301902 1930 19371937

Efficacy of Amphetamine

Hyperactive Child Syndrome

Morbid DefectMoral Control

19

How is ADHD Diagnosed?

20

How common is ADHD?

21

ADHD: Prevalence in Childhood

ADHD is one of the most common mental disorders in childhood

Conservative estimates of 3%-7% in grade school children– 4.4 million (7.8%) of 4-17 year-old US children

have a history of ADHD by parent report

CDC. MMWR. 2005;54:842-847.

22

What causes ADHD?

23

ADHD Risk Factors/Etiology

Genetics– Family studies– Twin & adoption studies– Molecular genetics

Biological Adversity– Maternal smoking– Alcohol exposure during pregnancy– Low birth-weight

Psychosocial Adversity

Biederman J. Biol Psychiatry. 2005;57:1215-1220.

24

25

Adults With ADHD Show Decreased Cerebral Metabolism

Global and regional glucose metabolism by PET scan is reduced in adults who have been hyperactive since childhoodLargest reductions in:

– Premotor cortex– Superior prefrontal

cortex

Copyright © 1990 Massachusetts Medical Society. All rights reserved. Zametkin AJ, et al. N Engl J Med 1990;323:1361-6.

Normal

With ADHD

26

Anterior Cingulate (Cognitive Division) Fails to Activatein Attention-Deficit/Hyperactivity Disorder

MGH-NMR Center & Harvard- MIT CITP Bush et al., 1999

1 x 10-3

1 x 10-2 1 x 10-2

1 x 10-3

Figure 3a.

y = +21 mm y = +21 mm

Normal Controls ADHD

27

Why treat ADHD?

28

PreschoolSchool-age

AdolescentCollege-age

Adult

Disruptive behavior

Academic failure Poor socialization Self-esteem issues Injuries

Low self-esteem Smoking Substance use Crime Car accidents

Academic failure Occupational failure Substance abuse

Relationship failures Poor work history Chronic substance

abuse and dependence Incarceration

Lifetime Impairments of ADHD

29

TreatmentsMedication– Stimulant– Nonstimulant

Education– www.aacap.org– www.aap.org– www.nimh.org– www.parentsmedguide.org

Community support (www.chadd.org)Behavioral interventionsSchool interventions

30

Medications for ADHD

FDA approved – Stimulants (methylphenidate, amphetamines)

FDA approved for use in children, adolescents and adults

– Non-stimulant (atomoxetine)FDA approved for use in children, adolescents and adults

– Non-stimulant (guanfacine XR & clonidine XR)FDA approved for use in children & adolescents

31

Multimodal Treatment of ADHD Study (MTA)

Arch Gen Psych 1999;56:1073-86

579 children 7-9.9 y.o., 14 months of treatmentMedication vs Intensive Behavioral vs Both vsCommunity ReferralFor ADHD symptoms, medication with & without behavioral therapy was superior to behavioral management aloneCombined treatment not significantly better than medication alone for acute core ADHD symptoms

32

Combined Treatment(Medication + Behavioral)

Gold standard Lower doses of medication can be usedParents preferred combination treatmentBenefits have been shown in:– Peer interactions– Parent-child relations– Academic achievement– Social skills– Aggression

Carlson CL, et al. J Abnorm Child Psychol 1992;20:213-32; The MTA Cooperative Group. Arch Gen Psychiatry 1999;56:1073-86.

33

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 psychopharmacologyOne of the most robust responses in pediatric psychopharmacology

34

AACAP ADHD Practice Parameters

Search covered 5,000 references over the period from 1996-2006AMA Council on Scientific Affairs– “Overall, ADHD is one

of the best-researched disorders in medicine..”

Pliszka, AACAP ADHD Practice Parameters JAACAP 2007

35

AACAP ADHD Practice Parameters: Stimulants

65-75% clinical response in DBPC trialsIf both MPH & AMPH are tried, initial response may be as high as 85%Effect size averaging about 1.0, one of the largest effects for any psychotropic medication


36

What is the best way to dose the medication?

37

Drug release technology: “biphasic” release profile with combination of intermediate release (IR) and

extended release (ER) MPH beads

Protective membrane

20 mg

Protectivemembrane

Release controlmembrane

MPH

Core

ER beads

CoreMPH

IR beads

Time Release Capsules

38

Water

Water

During operation

Orifice/exit port

Drugcompartment #1

Drugcompartment #2

Pushcompartment

Drugovercoat

Rate-controlledmembrane

Before operation

Oros® Technology

39

Concentrated drug-in-acrylic

for delivery

Concentrated drug-in-acrylic

for delivery

Methylphenidate Patch

40

Methylphenidate Patch

Applied to hip, for up to 9 hoursLag time– Package insert recommends application 2

hours before effect neededMajority of subjects in Phase III clinical efficacy study had minimal to definite erythema, generally not resulting in discontinuation

41

.

Methylphenidate Patch(Daytrana Package Insert, 2006)

Patch Size & Delivery Rate of Methylphenidate

Surface Area MPH Content per Patch Delivery Rate Dose of MPH delivered over 9-hours

12.5 cm2 27.5 mg 1.1 mg/hr 10 mg

18.75 cm2 41.3 mg 1.6 mg/hr 15 mg

25 cm2 55 mg 2.2 mg/hr 20 mg

37.5 cm2 82.5 mg 3.3 mg/hr 30 mg

42

Treatment Options—StimulantsMethylphenidate– Ritalin (methylphenidate)– Focalin (d-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

Amphetamine– Adderall, Dexedrine (d-amphetamine)– Extended release d,l-amphetamine (Adderall XR™):

biphasic (50% immediate, 50% 4 hours later)– Vyvanse (Lisdexamfetamine)

43

Side Effects of Stimulants

Appetite suppressionInsomniaGrowth suppressionCardiovascularRare: psychotic symptoms, mania

44

Pharmacotherapy cont’d

Non-stimulant Agents (only atomoxetine, guanfacine XR, and clonidine are FDA-

approved for ADHD)

– Atomoxetine (Strattera)– Guanfacine XR (Intuniv)– Clonidine XR (Kapvay) – Bupropion (Wellbutrin)– Desipramine (Norpramin)

45

Indications for Atomoxetine (Strattera)

FDA-approved for the treatment of children 6 years of age and older, adolescents, and adultsLow substance abuse liability, so often seen as an option where there is a high risk of substance abuse or diversionMay be useful for those with comorbid anxiety or comorbid Tourette’s

46

Side Effects & Side Effect Management of Atomoxetine

Stomach upset/vomiting SedationIrritabilityGrowthLiverSuicidality

47

Dosing of Atomoxetine

Dosed by body weight (which may change over time)Initiated at approximately 0.5mg/kg/day and gradually titrated to target dose (1.2 mg/kg/day)Dosing: AM vs PM vs BIDMaximum daily dose– Dosing guidance based upon dose-finding study– Recent high dose studies up to 2.4 & 3.0 mg/kg/d

demonstrated limited benefit of dosing above FDA approved maximum doses of 1.4 mg/kg/d (Kratochvil 2007, JAACAP)

48

Guanfacine XR (Intuniv)Approved for children & adolescents 6-17– Low substance abuse liability– May be helpful for co-occurring tics

Most common side effects– Somnolence (38%)– Headache (24%)– Fatigue (14%)– Upper abdominal pain (10%)– Nausea, lethargy, dizziness, low blood

pressure, irritability (each 6%)– Decreased appetite (5%)

49

Dosing of Guanfacine XR

Doses: 1mg, 2mg, 3mg, 4mgTitration is generally weeklyAdverse effects may dictate rate of titration

50

Clonidine XR (Kapvay)Dosing should be initiated with one 0.1 mg tablet at bedtime, and the daily dosage should be adjusted in increments of 0.1 mg/day at weekly intervals until the desired response is achieved. Doses should be taken twice a day, with either an equal or higher split dosage being given at bedtimeShould be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days.

Total Daily Dose

Morning Dose

Bedtime Dose

0.1 mg/day

0.1 mg

0.2 mg/day

0.1mg 0.1 mg

0.3 mg/day

0.1 mg 0.2 mg

0.4 mg/day

0.2 mg 0.2 mg

Kapvay Package Insert, 2010

51

What About Combining Alpha-2 Agonists & Stimulants?

In the past year 2 alpha-2 agonists have been approved as adjunctive therapy to stimulant medications– Guanfacine extended-release– Clonidine extended-release

52

Education

ParentsMedGuide.orgCH.A.D.D. (Children and Adults with Attention Deficit Disorders)– national organization with 32,000 members

&500 chapters– support and information about parenting, life

skills, school success, medical information, and legal rights

– www.chadd.org

53

Dosing Outside of School

• Evenings• Weekends• Summers

54

Are there other problems that frequently go along with ADHD?

55

Comorbidity Often Complicates the Diagnosis and Treatment of ADHD

ADHD alone 31% OppositionalDefiant

Disorder40%

Anxiety/MoodDisorders

38%ConductDisorder 14%

n=579

Tic Disorder11%

ADHD

31%

Jensen P, et al. Arch Gen Psychiatry 1999;56:1073-1086.

56

Practice Parameters for the Assessment & Treatment of Children & Adolescents with ADHD

ADHD frequently comorbid with other psychiatric disorders54-84% will meet criteria for oppositional defiant disorder15-19% will start to smoke or develop other substance disorders25-35% will have learning or language problemsUp to 1/3 will have anxiety disorders

57

Comorbidities

The rule, rather than the exceptionCan impact level of impairmentAvailable pharmacotherapies are very effective. If several well-delivered interventions fail, reconsider a comorbidityIf a previously effective medication becomes ineffective, consider first noncompliance, then potentially a new-onset comorbidity

58

Meta-Analysis: Tx of ADHD with Comorbid Tic Disorder

Meta-analysis of 9 studies, 477 subjectsD-amph, MPH, α-2 agonists, desipramine, ATMMPH, α-2 agonists, desipramine, and ATMX demonstrated efficacy in improving ADHD symptoms in children with comorbid ticsα-2 agonists & ATMX improved comorbid ticsMPH greatest & most immediate improvement of ADHD & didn’t worsen ticsα-2 agonists best combined treatment

Bloch et al, JAACAP September 2009

59

Do children with ADHD outgrow ADHD?

60

ADHD: Course of the Disorder

Inattention

Time

Hyperactivity

Impulsivity

61

ADHD: A Lifelong Disorder

Adults with ADHD

Adolescents with ADHD

Children with ADHD

Prevalence in juvenile population6%-9%

Prevalence in adult population 3%-5%

50% persists

into adulthood

75%persists

intoadolescence

Wilens TE. Psychiatr Clin North Am. 2004;27:283-301.

62

What about ADHD in young children?

63

Growing use of Psychostimulants(Zito et al, JAMA, 2000)

Review of two medicaid programs and one managed care organization1.23%, 0.89%, and 0.51%, respectively, of all children 2-4 years of age enrolled in these programs were receiving stimulant medications (primarily methylphenidate)Reflected a 3 fold, 1.7 fold, and 3.1 fold increase from 1991 to 1995

64

Preschool ADHD Treatment Study (PATS)

303 children, ages 3 to 5.5 years165 were treated with MPH, starting at 1.25mg TIDMean optimal total daily dose 14.2 mg/d, + 8.1 (0.75 mg/kg/d)All 3 doses significantly reduced ADHD symptoms, effect sizes 0.4-0.8, although no doses > 7.5mg TID givenEmotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability were most frequently reported adverse effects

Greenhill et al, JAACAP, 2006

65

FDA Approval vs Clinical Research Data

• Dextroamphetamine is approved for children 3 years of age and older– Open-label report

• Methylphenidate is approved for children 6 years of age and older– The only pharmacotherapy with controlled

study data available on children under 6– Package insert specifically warns against use

in children under 6

66

Atomoxetine vs. Placebo for the Treatment of ADHD in 5- and 6-year-old

ChildrenKratochvil et al, Pediatrics 2011

Study Design: Three sites conducted the 8-week, DBPC study of atomoxetine in 101 young children, 5- to 6-years-of-age, with ADHD.

67

Conclusion

This study offers the first controlled data on the use of ATMX in children as young as 5 years of age.ATMX was generally well-tolerated and reduced core ADHD symptoms as rated by parents and teachers.Long-term studies are neededDespite benefits, the atomoxetine group overall remained significantly impaired at the end of the study

68

I have heard that these medications effect growth, is

that true?

69

ADHD Pharmacotherapy & Growth

Concerns throughout past 3-4 decades– Safer, Allen, Barr, Depression of growth in

hyperactive children on stimulant drugs, NEJM 1972

– Charach et al, Stimulant treatment over 5 years: effects on growth, JAACAP, 2006

Potentially kids with ADHD have different growth trajectories– Spencer et al, Growth deficits in children with

ADHD, Pediatrics, 1998

70

ADHD Pharmacotherapy & Growth

MTA Cooperative Group, NIMH MTA Follow-up: changes in effectiveness and growth after the end of treatment Pediatrics, 2004; 2006– Reduced growth after 24 & 36 months

Swanson et al, Stimulant-related reductions in growth rates in the PATS, JAACAP, 2006– At 1 year mean gains -1.38cm & -1.3 kg

Kratochvil et al, Effects of Long-term Atomoxetine Treatment for Young Children with ADHD, JAACAP, 2006– 6 & 7 y.o., -2.9 cm at 18 mo, -2.5kg, level off at 24 mo

Spencer et al, 5-year Effects of Atomoxetine on Growth in Children with ADHD– Maximum short-fall in weight at 12 mo, +1.1kg & +0.3cm at yr 5

71

Practical Considerations Regarding Height & Weight Monitoring

Must monitor longitudinally, looking for outliers with clinically significant changes

Education regarding diet and calorie supplementation

Routine monitoring of height and weight

Growth charts– http://www.cdc.gov/growthcharts/

Continue to assess the risk-benefit relationship

72

What role does substance abuse play in ADHD?

73

Earlier Initiation of Smoking with ADHD

6- to 17-year-old boys

0.6

0.5

0.4

0.3

0.2

0.1

0

Smok

ing

prob

abili

ty

0 2 4 6 8 10 12 14 16 18 20 22 24P<0.003

ADHD n=128Control n=109

Milberger S, et al. J Am Acad Child Adolesc Psychol. 1997;36:37-44.

74

Pharmacotherapy of ADHD in the Context of Substance Abuse

Extended-release guanfacine & clonidineAtomoxetineBupropion*Modafinil*Lisdexamfetamine

*Not FDA approved for ADHD

75

I heard that there is a risk of heart problems with these medications, is that true?

76

Cardiovascular WarningsStimulants should generally not be used in children, adolescents, or adults with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems.Use with caution in treating patients with underlying medical conditions that might be compromised by increases in blood pressure or heart rate such as those with pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia. Before initiating treatment, patients should have careful history and physical exam to assess for presence of cardiac disease.

These warnings were required by the FDA for all CNS stimulant products to treat ADHD in May 2006.Focalin XR [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2006.

77

Recommended Cardiovascular Monitoring

American Heart Association Guidelines History– Family history of sudden death (<30 yrs of age for children;

<50 yrs of age with MI for adults)– Congenital or acquired cardiac structural defects– Syncope– Chest pain– Palpitations

Check BP/pulseMonitor above during treatmentNo need for ECG, echocardiogram in routine cases

Gutgesell H, et al. Circulation. 1999;99:979-982.Dulcan M. J Am Acad Child Adoles Psych; 1997;36(10 suppl):85S-121S.Wilens TE, et al. Pediatrics 2006;118:1215-1219.

78

Recent Cardiovascular Data:

Journal of the American Medical AssociationAmerican Journal of PsychiatryPediatricsNew England Journal of Medicine

79

Stimulant Dosing

No studies examining MPH or AMPH doses in children or adolescents above 60mg/d, or 72mg OROSOn average linear dose-response relationship, with no evidence of a global “therapeutic” window


80

MPH Dosing Guidelines for Pediatric Patients

U.S. FDA: maximum 60 mg/day for short-acting MPH and 72 mg/day for extended-releaseAACAP Practice Parameters for ADHD: – “with careful clinical monitoring, these doses may be

exceeded in individual cases” (Pliszka et al. 2007)– “off-label max/day” of OROS MPH = 108 mg (Pliszka

et al. 2007)Others recommend weight-based dosing up to 1.5-2 mg/kg/day of MPH (e.g., Biederman et al. 2006)

81

Atomoxetine Dosing

Target dose of 1.2 mg/kg/dayMaximum dose 1.4 mg/kg/day, not to exceed 100mgMany of the early clinical trials dosed up to 1.8 mg/kg/day

82

Off-Label Maximum Dose/DayAmphetamine preparations– Short & Long-acting- >50kg: 60mg– Lisdexamfetamine- unknown (FDA approved max

70mg)Methylphenidate– Short & Long-acting- >50kg: 100mg– D-methylphenidate- 50mg– OROS-methylphenidate- 108mg– Daytrana- unknown (FDA approved max 30mg)

Atomoxetine– Lesser of 1.8 mg/kg/d or 100mg


83

Dosing Conclusions

Current dose recommendations are appropriate for most patientsNo systematic advantage to increasing atomoxetine beyond current guidelinesContinued treatment, whether at higher dose or previous dose, associated with improved outcome in patients who demonstrated inadequate response to acute ADHD treatment after 6-8 weeks

84

Meta-Analysis: Tx of ADHD with Comorbid Tic Disorder

Meta-analysis of 9 studies, 477 subjectsD-amph, MPH, α-2 agonists, desipramine, ATMX, deprenylMPH, α-2 agonists, desipramine, and ATMX demonstrated efficacy in improving ADHD symptoms in children with comorbid ticsα-2 agonists & ATMX improved comorbid ticsMPH greatest & most immediate improvement of ADHD & didn’t worsen ticsα-2 agonists best combined treatment

Bloch et al, JAACAP September 2009

85

Clonidine: Alone & Combined with MPH for ADHD

16-week, randomized, DBPC trial of 122 children 7-12 y.o. with ADHDClonidine vs MPH vs Clonidine/MPH vs PBOConners ASQ-T primary outcome: – Only MPH & Clonidine/MPH significantly better than

PBO– ES Clonidine 0.17; MPH 0.41; COMB 0.73

Secondary measures (ASQ-P, CGAS) suggested benefit of clonidine

Palumbo et al, JAACAP 2008

1

Christopher J. McDougle, MDDirector, Lurie Center for Autism

Professor of Psychiatry and PediatricsMassachusetts General Hospital and MassGeneral Hospital for Children

Nancy Lurie Marks ProfessorHarvard Medical School

Psychopharmacology of

Autism

2

Disclosure of Financial Interests

- Nothing to disclose

3

Off-Label Use Of Medication

In this presentation, all discussion of use of medication refers to “off-label” use other than risperidone and aripiprazole for irritability in children and adolescents with autistic disorder

4

Learning Objectives

Identify target symptoms for drug therapy in autism spectrum disorders.

Discuss results from controlled drug studies in the treatment of autism spectrum disorders.

Discuss the potential adverse effects associated with drugs used in the treatment of autism spectrum disorders.

5

Pervasive Developmental Disorders

Autistic Disorder Asperger’s Disorder Rett’s Disorder Childhood Disintegrative Disorder Pervasive Developmental Disorder Not

Otherwise Specified

6

7

Potential Targets of Pharmacotherapy

1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury, severe

trantrums) 4. Impaired social relatedness5. Sleep disturbance

8




9

Stimulants in Autism Historical data and beliefs negative Small studies support use of MPH in

autism1,2

Anecdotal reports of a high frequency of adverse drug effects including stereotypies and social withdrawal

MPH = methylphenidate.1Quintana H et al. J Autism Dev Disord. 1995;25:283-294.2Handen BL et al. J Autism Dev Disord. 2000;30:245-255.

10

RUPP Autism Network Study of MPH in Children With PDD + Hyperactivity

72 Children (age, 5–14 y) with autism, Asperger’s Disorder, or PDD NOS and significant “ADHD” symptoms

Study design 7-day test-dose period 4-week double-blind trial of 3 dose levels

(0.125, 0.25, 0.50 mg/kg/dose) of MPH TID and placebo in random order

PDDNOS = pervasive developmental disorder not otherwise specified.ADHD = attention deficit/hyperactivity disorder.RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.

11

Test-Dose Phase 6 out of 72 subjects were unable to

tolerate ≥2 dose levels of MPH and were dropped from the study

16 out of the remaining 66 subjects had intolerable adverse effects at the highest dose of MPH; entered modified crossover phase

Irritability was the most common reason for intolerability

RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.

12

Crossover Phase 58/66 subjects completed the crossover

phase 7 subjects dropped out due to intolerable

adverse effects There was a statistically significant main

effect of dose of MPH on the ABC Hyperactivity subscale score as rated by both teacher (Primary Outcome Measure; P =.009) and parent (P <.001)

ABC = Aberrant Behavior Checklist.RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.

13

Crossover Phase: Other ABC Subscales

Statistically significant worsening of parent-rated Social Withdrawal at high-dose MPH (P <0.0001)

No statistically significant changes in other subscales (Irritability, Stereotypy, Inappropriate Speech)

ABC = Aberrant Behavior Checklist.RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274

14

Categorical Response 44 subjects were rated as responders to at least 1

week of treatment (MPH or placebo): MPH (n = 35), Placebo (n=9)

Subject age, IQ, *diagnosis (trend, P =.07), and weight did not moderate treatment response

*Subjects diagnosed with Asperger’s disorder and PDD NOS were more likely to be classified as responders to both placebo and MPH than those with autism


15

Categorical ResponsePlacebo Low Medium High

Asperger’s disorder/ 6 (32%) 7 (37%) 7 (37%) 6 (32%) PDD NOS (n=19)

Autism (n=47) 6 (13%) 13 (28%) 15 (32%) 12 (26%)

Response to each dose of MPH was superior to placebo for autism subgroup (P <.001), but not for the Asperger’s disorder/PDD NOS subgroup (P >.05)


16

MPH Summary

35/72 subjects (49%) responded to MPH

13/72 (18%) exposed to MPH dropped out due to adverse events


17

Treating Hyperactivity: Other Medications

Clonidine efficacious in 2 small placebo-controlled trials1,2

Open-label guanfacine in RUPP MPH nonresponders is positive, suggesting that guanfacine may be an alternative3

Encouraging open-label and controlled crossover design data with atomoxetine

1Jaselskis CA et al. J Clin Psychopharmacol. 1992;12:322-327.2Fankhauser MP et al. J Clin Psychiatry. 1992;53:77-82.3Scahill L et al. J Child Adolesc Psychopharmacol. 2006;16(5):589-5984Posey DJ et al. J Child Adolesc Psychopharmacol, 2006; 16(5):599-610. .

18

19



tantrums)4. Impaired social relatedness 5. Sleep disturbance

20

Serotonin Reuptake Inhibitors (SRIs)

Rationale for studying SRIs in autism

Similarities to obsessive-compulsive disorder

Serotonin abnormalities in autism

21

SRIs in Autism for Repetitive Behavior

Clomipramine better than placebo and desipramine in children and young adults with autism1

Fluvoxamine better than placebo in ADULTSwith autism2

Fluvoxamine no better than placebo and poorly tolerated in CHILDREN with PDDs3

Fluoxetine better than placebo and well tolerated in children with PDDs4

1Gordon CT et al. Arch Gen Psychiatry. 1993;50:441-447.2McDougle CJ et al. Arch Gen Psychiatry. 1996;53:1001-1008.3McDougle CJ. Unpublished data. 4Hollander E et al. Neuropsychopharmacology. 2005; 30:582-589.

22

Citalopram in PDDs 149 children (9.4 ± 3.1 years) with PDDs and significant

repetitive behavior 12-week, double-blind, placebo-controlled, parallel groups

design Citalopram started at 2.5 mg/day; max dose = 20 mg/day;

(mean dose = 16.5 ± 6.5 mg/day) No drug-placebo difference in response on CGI-I or in score

reduction on CY-BOCS-PDD Significantly more adverse events with citalopram than

placebo: increased energy level, impulsiveness, decreased concentration, hyperactivity, stereotypy, diarrhea, insomnia, and dry skin or pruritus

King BH et al. Arch Gen Psychiatry. 2009; 66(6):583-590.

23

ACTN Study of Fluoxetine in Autism: S O F I A

14-week, double-blind, placebo-controlled Largest trial of SSRI in autism to date 158 subjects, ages 5-17 y Fluoxetine not effective for repetitive

behaviors in youth with autism vs. placebo

ACTN = Autism Clinical Trials NetworkAutism Speaks, press release 2009

24

25


1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury,

severe tantrums) 4. Impaired social relatedness 5. Sleep Disturbance

26

Typical Antipsychotics

Several RCTs of haloperidol associated with improvement in a variety of symptoms including aggression and irritability

Adverse effects: dystonia, dyskinesias

RCT = randomized clinical trial.Anderson LT et al. Am J Psychiatry. 1984;141:1195-1202.Campbell M et al. J Am Acad Child Adolesc Psychiatry. 1997;36:835-843.

27

Atypical Antipsychotics

Serotonin antagonism in addition to dopamine antagonism

Lower risk of dyskinesias Individual drugs include

Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Paliperidone

28

Clozapine

Case reports only Can lower the seizure threshold Risk of agranulocytosis

Frequent blood draws necessary

29

30

Risperidone in Children With Autism and Serious Behavioral

ProblemsRUPP Autism Network

Indiana University (Christopher J. McDougle, MD)Kennedy-Kreiger, Johns Hopkins (Elaine Tierney, MD)

Ohio State University (Michael G. Aman, PhD; L. Eugene Arnold, MD)Yale Child Study Center (Larry Scahill, MSN, PhD)

UCLA (James T. McCracken, MD)NIMH (Benedetto Vitiello, MD)

31

Acute Risperidone Trial: RUPP in Children and Adolescents 101 subjects (82 boys, 19 girls) Diagnosis: autistic disorder Significant irritability (ABC Irritability ≥18) 8 weeks, double-blind, placebo-controlled,

parallel groups Mean age = 8.8 ± 2.7 y; range = 5–17 y Risperidone 1.8 mg/d; range = 0.5–3.5 mg/d

RUPP Autism Network. N Engl J Med. 2002;347:314-321.

32

Acute Risperidone Trial: RUPP

12%

69%

0

20

40

60

80

100

Risperidone Placebo

Percent Responding

Response criteria: ≥25% improvement in the ABC-I score, and a rating of “much improved” or “very much improved” on the CGI-I

(34/49)

(6/52)

P < 0.001

ABC-I = Aberrant Behavior Checklist–Irritability.CGI-I = Clinical Global Impressions–Improvement.RUPP Autism Network. N Engl J Med. 2002;347:314-321.

33

Acute Risperidone Trial: RUPP Adverse effects Mean increase in weight

Risperidone, 2.7 ± 2.9 kg Placebo, 0.8 ± 2.2 kg; P < 0.001

Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group; all P < 0.05

AIMS and Simpson-Angus: no EPS

AIMS = Abnormal Involuntary Movement Scale.EPS = extrapyramidal symptoms.RUPP Autism Network. N Engl J Med. 2002;347:314-321.

34

Baseline and Endpoint ABC Scores by Group

Risperidone PlaceboABC Baseline Endpoint Baseline EndpointIrritabilityP < 0.001

26.2 (7.9) 11.3 (7.4) 25.5 (6.6) 21.9 (9.5)

Social WithdrawalP = 0.03/NS

16.4 (8.2) 8.9 (6.4) 16.1 (8.7) 12.0 (8.3)

StereotypyP < 0.001

10.6 (4.9) 5.8 (4.6) 9.0 (4.4) 7.3 (4.8)

HyperactivityP < 0.001

31.8 (9.6) 17.0 (9.7) 32.3 (8.5) 27.6 (10.6)

InappropriateSpeechP = 0.03/NS

4.8 (4.1) 3.0 (3.1) 6.5 (3.6) 5.9 (3.8)

RUPP Autism Network. N Engl J Med. 2002;347:314-321.

35

RUPP Risperidone –Parent Management Training

Trial 124 children (4 to 13 years) with PDDs and

significant irritability 24-week, three-site, randomized, parallel

groups trial Children randomized 3:2 to COMB (n=75) or

MED (n=49) Parents in COMB received a mean of 10.9

PMT sessionsRUPP Autism Network. J Am Acad Child Adolesc Psychiatry. 2009;48(2):1143-1154.

36

RUPP Risperidone –Parent Management Training

Trial

Primary Outcome Measure (Home Situations Questionnaire [HSQ]); COMB > MED (P=.006)

COMB > MED on ABC Irritability (P=.01), Stereotypic Behavior (P=.04), and Hyperactivity/Noncompliance (P=.04)

Final Risperidone dose for MED (2.26 mg/day) vs. COMB (1.98 mg/day) (P=.04)

ABC = Aberrant Behavior Checklist.RUPP Autism Network. J Am Acad Child Adolesc Psychiatry. 2009;48(2):1143-1154.

37

38

Olanzapine – Double-Blind, Placebo Controlled Study

11 children with pervasive developmental disorders (9 y)

8-week, double-blind, placebo-controlled Olanzapine 10 ± 2.04 mg/d Response: Olanzapine 3/6 Placebo 1/5 Weight Gain: Olanzapine 7.5 ± 4.8 lbs

Placebo 1.5 ± 1.5 lbs

Hollander E et al. J Child Adolesc Psychopharmacol. 2006;16(5):541-548.

39

Quetiapine - Ziprasidone

No placebo controlled data with either drug

Quetiapine: sedation

Ziprasidone: less weight gain; potential ECG effects

40

Aripiprazole in Autism –Flexible Dose Study

98 children and adolescents with autism (age 6-17 years) with significant irritability

8-week, double-blind, placebo-controlled, parallel groups, flexibly-dosed (2-15 mg/day) trial

Aripiprazole (8.5 mg/day) more efficacious than placebo on Aberrant Behavior Checklist Irritability subscale (P<.001)

Discontinuation rates: PLA=5.9% Aripiprazole=10.6% Most common AEs with aripiprazole were fatigue and

somnolence Weight gain PLA=1.0 kg Aripiprazlole=2.1 kg

Owen et al. Pediatrics. 2009;124(6):1533-1540.

41

Aripiprazole in Autism –Fixed Dose Study

218 children and adolescents with autism (age 6-17 years) with significant irritability

8-week, double-blind, placebo-controlled, parallel groups, fixed-dose (5 mg, 10 mg, 15 mg) trial

Aripiprazole (5 mg, 10 mg, 15 mg) more efficacious than placebo on Aberrant Behavior Checklist Irritability subscale (P<.05 for all)

Discontinuation rates: PLA=7.7%, 5 mg=9.4%, 10 mg=13.6%, 15 mg=7.4 %

Common AEs leading to discontinuation: sedation, drooling, tremor, akathisia, EPS

Weight gain PLA=0.3 kg, 5+10 mg=1.3 kg, 15 mg=1.4 kg

Marcus et al. J Am Acad Child Adolesc Psychiatry. 2009;48(11):1110-1119.

42

Aripiprazole in Autism –52-Week, Open-Label Study

52-week, open-label, flexible dose (2-15 mg/day), long-term study

Subjects enrolled from two 8-week RCTs or as de novo subjects 303 subjects (de novo n=86, prior aripiprazole n=174, prior

placebo n=70) received treatment. 199 subjects (60.3%) completed 52 weeks of treatment

Mean dose of aripiprazole = 9.6 mg/day The majority of subjects maintained response (CGI-I = 1 or 2)

throughout the 52-week study 6.1% of subjects discontinued due to lack of efficacy; 10.6% of

subjects discontinued due to adverse effects (aggression and weight increase)

Marcus et al. J Child Adolesc Psychopharmacol 2011; 21(3):229-236.

43

44

Paliperidone for Irritability in Adolescents and Young Adults with Autism:

Preliminary Results

8-week, prospective, open-label study 25 subjects enrolled; mean age=15.2 y (12-21 y); IQ = 50

Concomitant meds allowed; stable for 2 mos prior to study Mean dose, 6.9 mg/d; range, 3-9 mg/d

83% (20/24) responded based on CGI-I and ABC-I Two exited early [nonresponse (1); moderate sedation (1)]

Mean weight gain 2.3 kg (-3.6 to +7.9 kg); Mean change in age- and sex-normed BMI: 23.1 (BL) to 23.8 (Endpoint)

Stigler et al. Preliminary data from poster presentation at 2010 APA.

45Stigler et al. Preliminary data from poster presentation at 2010 APA.

Paliperidone for Irritability in Adolescents and Young Adults with Autism:

Preliminary Results

46

47



tantrums)4. Impaired social relatedness 5. Sleep disturbance

48

Medications Studied for Social Impairment in Autism Not effective

Fenfluramine Naltrexone Lamotrigine Amantadine Risperidone Fluoxetine Citalopram

49

D-Cycloserine in Children with Autism

80 children (6.5 ± 2.8 years; range 3-12 years) with autistic disorder and significant social withdrawal

8-week, double-blind, placebo-controlled, parallel groups design

D-cycloserine 1.7 mg/kg/day divided twice daily or placebo

No drug-placebo difference on the CGI-I, ABC Social Withdrawal subscale, or Social Responsiveness Scale

D-cycloserine generally well-tolerated Majority of responders maintained response during

16-week open-label extension Posey DJ et al. AACAP Poster 3.53, 2008.

50




51

Medications for Sleep Disturbance

Melatonin Clonidine Trazodone Mirtazapine Hydroxyzine Doxepin Diphenhydramine and Benzodiazepines

(paradoxical reaction, disinhibition)

52

Complementary and Alternative Medicine (CAM)

Secretin Gluten-free and Casein-free diet Oral Immunoglobulin Omega-3 fatty acids Vitamin B6/Magnesium

53

Future Directions Motor Hyperactivity/Inattention

- Double-blind, placebo-controlled trial of atomoxetine- Double-blind, placebo-controlled trial of guanfacine

Repetitive Behavior- Pilot studies of riluzole

Aggression, Self-Injury, Property Destruction- Controlled trial of paliperidone

Impaired Social Relatedness- Controlled trial of D-cycloserine + Social Skills Training- Double-blind, placebo-controlled trial of memantine- Pilot studies of intranasal oxytocin

54

55

Questions??

1

Treatment of Children and Adolescents

with Anxiety Disorders

John T. Walkup, MDDivision of Child and Adolescent Psychiatry

Weill Cornell Medical CollegeNew York, NY

2

Disclosure: John T. Walkup, MD

Consultant Advisory Board

Speaker’s Bureau

Honorarium or Expenses Paid to Attend Meeting

Research Contract Royalties

AACAP X

Shire X

Pfizer XDrug and PBO

Abbott XDrug

LillyX

Drug and PBO

TouretteSyndrome

Assoc. X X X

Oxford PressGuilford Press X

3

Learning Objectives

At the conclusion of this activity, the participant should be able to: identify the evidence base for treatment

of childhood anxiety disorders. construct medication augmentation

strategies for childhood anxiety disorders discuss behavioral approaches to

managing childhood anxiety disorder in office practice

4

Discussion of Off Label Use of Medications

All medications use should be considered off label unless explicitly noted otherwise

5

Introduction Review assessment of anxiety disorders

OCD (Coffey has this covered) Non-OCD Anxiety Disorders PTSD

The evidence base Beyond the evidence base CBT principles set the stage for a

medication trial

6

Bottom Line Antidepressants work extremely well

SSRIs medication of choice Atypical antidepressant should be considered second line,

but considered Some limited data on augmentation strategies Limited data for benzodiazepines No reason to expect that buspirone or bupropion should be

effective To do a good job will have to prescribe ‘off label’

CBT also extremely effective when done by a pro Outstanding med management and CBT principles

wonderfully complementary

7

Anxiety Disorders in Children and Adolescents Specific Phobia OCD Separation Anxiety Disorder Generalized Anxiety Disorder Social Phobia Acute Stress Disorder Post-traumatic stress disorder Panic Disorder

8

Anxiety is not a great term

Other terms capture the experience better Excessive interpersonal sensitivity Fear Apprehension Dread Excessive self-consciousness or shyness Worry

9

What to look for Physical complaints – headaches, stomach aches,

dramatic presentations of pain. Problems with falling asleep and middle of the night

awakening, Eating problems – over and under Avoidance of outside and interpersonal activities –

school, parties, camp, sleepovers, safe strangers Excessive need for reassurance –bedtime, school,

storms, bad things happening Inattention and poor performance at school Explosive outbursts Not necessarily pervasive

10

Assessment Strategies

Global scales with anxiety subscales Child Behavior Checklist Behavioral Assessment System for Children

MASC SCARED (in your hand out)

11

Epidemiology

Very common up to 8-10% of kids Under diagnosed Under treated Need to look for it Probably the most common childhood

disorder and the prepubertal mood disorder

12

The Treatment of OCD

13

Treatment of OCD Cognitive-behavioral treatment SRIs effective for OCD

Clomipramine (TCA) Fluvoxamine Paroxetine Sertraline Fluoxetine Citalopram likely effective Escitalopram likely effective

All permutations Deep brain stimulation

14

Serotonin Reuptake Inhibitors FDA Approvals

Approved for OCD Clomipramine > 10 yrs Fluvoxamine > 8 yrs Sertraline > 6 yrs Fluoxetine > OCD

Approved for Depression Fluoxetine > 12 yrs Escitalopram > 12 yrs

Approved for Non-OCD Anxiety None

15

SRI Efficacy for Non-OCD Anxiety Disorders

SAD, GAD and SoP Fluvoxamine – RUPP, 2001 Fluoxetine – Birmaher et al, 2003 CAMS – Walkup et al, 2009

SoP Paroxetine - Wagner et al, 2004 Fluoxetine - Beidel et al 2007 Venlafaxine - March et al, 2007-

GAD Sertraline - Rynn et al., 2001 Venlafaxine, Rynn et al., 2007 Buspirone in GAD, unpublished negative trial

16

Child/Adolescent Anxiety Multimodal Study (CAMS)

NIMH-funded SAD, GAD and SoP, N=488 12 weeks; COMB vs Med vs CBT vs PBO Results

COMB 81% CBT 59% SRT 56% PBO 24%

17

Other CAMS OutcomesYounger kids with anxiety do best with all

treatments.. Medication is well tolerated, but younger kids

also have more side effects – endpoint dose sertraline 130-40 mg/day (highest safe dose).

Technical expertise required for optimal dosing or risk under treatment and poor outcome

Adolescents likely require psychosocial rehab.

18

Other anxiety disorders

Very limited data

19

Dosing of SSRIs

Use clinical trials for timing of dose changes and maximum safe doses e.g. Fluoxetine up to 40 mg by week 12 (TADS,

2004) Fluvoxamine 100-150 mg by week 10

(RUPP, 2001) Sertraline 100-150 mg by week 8 (CAMS,

2009) Paroxetine 40-50 mg by week 10 (Geller,

2004)

20

Adverse Events of SSRIs

Activation is common 10-15% Early in course or after dose change – think

diphenhydramine Younger kids “Minimal brain dysfunction”

Bipolar switches uncommon <1% - later Frontal lobes symptoms at higher doses GI issues early Easy bruising and bloody noses Some case reports about growth

21

Suicidality – Benefit/Risk

% Difference for Efficacy MDD - 11.0% = NNT of 10 (3 for NIH Studies) OCD - 19.8% = NNT of 5 Non-OCD anxiety disorders - 37.1% = NNT of 3

% Difference for Suicidality 1-2% = NNH 50-100 (Hammad et al., 2006) 0.7% = NNH 143 (Bridge et al., 2007)

But not for individual disorders MDD - 0.9%; NNH ~100 OCD - 0.5%; NNH ~200 non-OCD anxiety disorders - 0.7% ; NNH ~140

22

What to do about activation?

23


Psychoeducation Early in treatment or right after dose

change 24-72 hours (think diphenhydramine)

Late activation? Prob unrecognized early activation

Stop immediately Doesn’t go away with time Won’t get to treatment dose False alarms

24


Switch Second SSRI Non-activating antidepressant No evidence that any non-antidepressant

will be useful

25

Non-activating Antidepressants*

Mirtazapine (Remeron) Duloxetine (Cymbalta) Nefazadone* (Serzone) TCAs

Nortriptyline (Pamelor) Clomipramine (Anafranil) Desipramine (Norpramin)

* With some exceptions - NE reuptake inhibitors may cause an initial anxious reaction that goes away with time

26

Medication Augmentation Strategies

Clomipramine Clonazepam Neuroleptics IV Clomipramine Buspirone Add second SSRI Lithium Stimulants Psychotherapy augmentation – d-cycloserine

March J, et al. Expert consensus guidelines: treatment of obsessive-compulsive disorder. J Clin Psychiatry. 1997;58(1-72).

27

Augmentation vs. Adjunctive

Augmentation e.g. Li addition to antidepressants

Serotonergically sensitize the brain, then “turbocharge” with addition of another 5-HT med

Lithium will not work alone Lithium does not work when started first

Adjunctive treatment e.g SSRI + BZD

28

Strategies for Partial Responsein OCD

Clomipramine Clonazepam Neuroleptics IV Clomipramine Buspirone Add second SSRI Lithium Stimulants Glutaminergic agents Others….. Psychotherapy augmentation – d-cycloserine

29

Enhancing Response No disruption

Adjust dose or add psychotherapy Low disruption

Add new medication (augmentation) Medium disruption

Intensive psychotherapy Large disruption

Change SRI

30

Clomipramine Augmentation

Low dose 10-50 mg/day Pharmacokinetic and pharmacodynamic

interaction

Higher doses Additive effects

Monitor side effects HR, BP, EKG

31

Clonazepam

Not true augmentation Adjunctive treatment You pick the dose up to 4-6 mg/daily Long titration periods as per

32

Risperidone Augmentation

Controlled trial suggest that neuroleptics can be useful for tics and schizotypy and OCD

Also good for anxiety and mood Some case reports of worsening of

OCD

33

IV Clomipramine

CMI = +++ serotonergic DesmethylCMI = +++ noradrenergic CMI to DCMI significant first pass

metabolism IV CMI bypasses the liver Effective for treatment resistant OCD

CMI + low dose FluvoxamineSallee et al. 1997

34

Severe OCD Check EKG etc Start with clomipramine, not SSRI Check levels and EKG

Good levels consistent with good side effect management Check CMI:DCMI ratio

If>1 no problem If<1 consider adding low dose fluvoxamine

Add low dose fluvoxamine (Vendel et al. 1995) Check levels to assure levels still in appropriate range Check to see that CMI:DCMI ratio >1 Check EKGs to make sure nothing changed significantly

Repeat steps above until ….

35

Two SSRIs or SSRI and SNRI

Partial response to one Cross taper to a second one (SSRI or

SNRI) Looks good on two SSRIs (quickly) Next steps?

Don’t necessarily discontinue first SSRI

36

Add a Second SSRI Logical Pharmacokinetic and pharmacodynamic

interaction Most will tolerate, but some will not Use short half-life SSRIs

37

Switching SSRIs

Time

OCD

Con

trol

Discontinue med Start new med

38

Switching SSRIs – Stopping old med too soon

Time

OCD

Con

trol

Discontinue old med here

Start new med

39

Second drug offering improved benefit

Don’t cut old med dose

Start new med

D’C first med

Time

OCD

Con

trol

40

Second drug augments first drug but didn’t

d’c first drug


Start new med

Didn’t D’C first med

Time

OCD

Con

trol

41

Risk for Serotonergic Side Effects by Combining SSRIS


Start new med

Didn’t D’C first med

TimeSer

oton

ergi

c S

ide

Effe

ct

42

Lithium Augmentation

No controlled trials Excellent for comorbid depression Good third drug

43

Buspirone Augmentation

Lack of support from controlled trials Some clinicians swear by it High doses? Is there a small sub group of patients

who respond?

44

Stimulants Good for SSRI-induced apathy Good for ADHD Good for mood disorders

45

D-cycloserine

Partial NMDA agonist Facilitates extinction of learned fear in

rats. Small positive studies for social anxiety

disorder (e.g. Storch et al., 2010) Lots to learn

Dose Duration Timing

46

N-Acetyl cysteine (Mucomyst) Involved in glutathione synthesis Glutathione is the predominant anti-oxidant

in the cytoplasm Mucolytic properties as in its use in CF Glutathione is one of the detoxifiers of

acetomenophen and is used to treat OD because loss of glutathione results in cell death.

NAC supplementation increase glutathione and its antioxidant properties

Augment for OCD or trich etc..

47

Glutaminergic Agents

Neuroprotective agents Riluzole Memantine

Wait and see

48

Other Strategies

Pindolol Inositol

Herbal Kava? But not St. John's wort, valerian,

Sympathyl, or passionflower

49

Summary

SSRIs and other antidepressants are effective

Worry about activation (think diphenhydramine type reaction)

Consider non activating antidepressants in those at risk

Risk benefit ratio is very positive Augmentation strategies may be useful

50

CBT for Office Practice

Education about anxiety and avoidance Characteristics of the anxiety disorders The problem of avoidance The stakes are high

Trajectories of illness Poor lifelong adaptation and coping

The treatments are effective and straightforward, so should get to treatment early

51

Characteristics of Anxiety

Anxiety is not the best term. Anxiety is always present (behind the

scenes), but symptoms are usually triggered

Parents minimize impact of anxiety as it is “not always present”

Anxiety is not associated with the loss of ability to experience pleasure –anxious kids can have fun

52

The Problem with Avoidance

Avoidance leads to a temporary reduction in anxiety but anxiety returns leading to worsening avoidance and anxiety – negative reinforcement

Parental accommodation of anxiety makes it worse too

Reassurance without action is not helpful Avoidance limits the development of

other coping and adaptation skills.

53

The Stakes are High

Three trajectories Anxiety early that doesn’t persist Persistent anxiety into adulthood Anxiety morphs into depression and

depression is associated with other adult mood disorders

Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety and depressive disorders in adolescents with anxiety and depressive disorders. Arch Gen Psychiatry. 1998 Jan;55(1):56-64. PubMed PMID: 9435761

54

The Stakes are High

Very early onset of symptoms – the prepubertal affective disorder

Early coping and adaptation is stunted (and maybe physical growth too!)

Hard to learn in later in life what was supposed to be learned in childhood

The treatments are effective so why not identify and treat early!

55

Do you want to start really early!!?!?!?

Screen parents of newborns for anxiety and depression

Look for signs of anxiety early Behavioral inhibition Sleep disturbance Gastrointestinal and other physical

symptoms Emotional dysregulation prior to puberty

56


The Anxiety Triad Thoughts, feelings, behavior

Can impact all three by starting with any one Thoughts – anxious bias to neutral event Feeling – discomfort and distress Behavior – avoidance

If you change the behavior the feelings and thoughts will follow.

57

CBT Resistant Symptoms

Symptoms sustained by reinforcement patterns other than internal negative reinforcement

58

Types of Reinforcement

PositiveReinforcement

Negative Reinforcement

InternallyReinforcing

Provides gratification Relieves distress

ExternallyReinforcing

Attention and support Avoidance

59

Key motivational principles and phrases

“Just do it” Be a hero, brave Take the challenge, tough it out Overcome adversity Get anxiety and fear out of your life

60

Key elements for treatment

Target parents as the agent of change They don’t really know what to do Intuitively, parents support avoidance

coping and accommodate to the child’s anxiety – “looking under the bed…”

Kids can’t change without their parents’ support

If parents don’t get on board, then referral is necessary.

61

Key elements for treatment

Child buy in Anxiety is a problem that can be fixed, no

need to suffer Identify how child is negatively affected by

anxiety – how it gets in the way. Make a friend – give the child credit when

they are doing things even when it is very difficult for them.

62


The problem with manuals Based on manuals used in research Your clinical evaluation should introduce

CBT principles

The Behavior Plan Make a list of things avoided Make a plan to do the simple things first Progress to more difficult challenges Lots of praise and support

63

Function-based Treatments

Do the four quadrants as part of the evaluation

Re-structure patterns of parent-child interactions

Often helpful to do in the context of restructuring the daily routine…

64

What to do?

Step 1 Start with meds when symptoms are severe Start with CBT when symptoms are milder or of

shorter duration Start with combined when available and when the

best outcome is desired

If absolutely no response to Step 1 re-evaluate including assessment of adherence

65

What to do? Step 2

When there is partial response to Step 1 Maximize med (maximum safe dose) and

add CBT Maximize CBT (in vivo exposures) and add

med Evaluate function of anxiety symptoms

when combination treatment is lagging Assess internal positive reinforcement of OCD Address parents’ inadvertent reinforcement of

OCD symptoms

66

What to do? Step 3 Meds

Medication augmentation Add antipsychotic if tics/sensory motor

symptoms or schizotypy present Add serotonergic agonist

Second SSRI if OCD remains the target Li if depression is prominent Other serotonergic agonists??

67

What to do? Step 3 CBT

Re-evaluate readiness for change Use in vivo exposures Use function based interventions

Family intervention to reduce inadvertant reinforcement of OCD

Individual intervention to reduce internal positive reinforcement (increase cost of OCD symptoms)

68

Summary

Medication and CBT effective Get used to “off label” prescribing Augmentation strategies need to be

selected carefully Behavioral approaches can leverage

psychopharmacology

Update on Pharmacological Treatment of Pediatric Mood Disorders

Karen Dineen Wagner, MD, PhDMarie B. Gale Centennial Professor & Vice Chair

Department of Psychiatry & Behavioral SciencesDirector, Division of Child & Adolescent Psychiatry

University of Texas Medical BranchGalveston, Texas

Financial Disclosure 9/2011(Past 12 months)

Honoraria: UMB Medica, Quantia Communications, CME LLC, American Psychiatric Association, Nevada Psychiatric Association, Slack Inc, Mercy, Hospital Universitario Ramón y Cajal

Off-Label Use

Medications discussed in this presentation are off-label for the acute and maintenance

treatment of major depression in youth, with the exception of fluoxetine and escitalopram

are off-label for the treatment of bipolar I disorder, manic or mixed episodes in youth, with the exception of lithium, aripiprazole, quetiapine, risperidone and olanzapine

FDA Approval for Acute Treatment of Major Depressive Disorder

Medication Ages

Fluoxetine 8-17

Escitalopram 12-17

Controlled Pediatric Depression Trials

* On primary outcome measure **Individual trials negative(Emslie et al, 2002; 1997; 2008; March et al, 2004; Wagner et al, 2003; 2004 Berard et al, 2006; Keller et al, 2001; Emslie et al, 2006; 2007; Wagner et al, 2006; Rynn et al, 2002; Von Knorring et al, 2006; Rynn et al, 2002; www.fda.gov/cder/foi/esum/2004/20152s032_serzone)

Medication Ages Number of Studies

Positive* Studies

Citalopram 7-17 1Sertraline 6-17 2 (a priori pooled analysis)**

Negative*Studies

Citalopram 13-18 1Escitalopram 6-17 1Mirtazapine 7-18

7-182

Nefazadone 7-1712-17

2

Paroxetine 7-1712-1813-18

3

Venlafaxine 7-177-17

2

Meta-analysis of Antidepressant Trials Depression in Youth

Response Rates

Number Needed to

Treat (NNT)

Antidepressants 61% 10

Placebo 50%

Bridge JA et al, JAMA 2007; 297:1683-1696.

Meta-analysis of Antidepressant TrialsDepression in Youth

Number Needed to Treat (NNT)

Adolescents 8

Children 21

Tsapakis EM et al. British J Psychiatry, 2008; 193:10-17.

Predictors of Poorer Response to Acute Treatment Response

More severe depression Baseline suicidality Comorbid disorders (anxiety, substance abuse) Hopelessness Family conflict

Emslie GL et al, Psychiatric Annals 2011; 41: 223-229; Goldstein TR et al, JAACAP 2007; 46:820-830; Asarnow JR et al, JAACAP 2009; 48:330-339.

Meta-analysis of Antidepressant Trials Depression in Youth

Remission Rate

Antidepressants 30-40%

Bridge JA et al, JAMA 2007; 297:1683-1696.

Acute Antidepressant Response and Remission in Pediatric Depression

N=168Open label Fluoxetine

At week 4, a CDRS-R reduction of > 58% best discriminates remitters from non-remitters

(Tao et al, J Am Acad Child Adolesc Psychiatry, 2009; 48:71-78)

Continuation Treatment in TORDIA Trial

Week Remission Rates12 18%24 39%48 65%72 79%

Brent DA et al, JAMA 2008; 299:901-913; Emslie GT et al, Am J Psychiatry, 2010; 167:782-791; Vitiello B et al. J Clin Psychiatry 2011; 71:388-396.

Remission defined as: ≥ 3 weeks with ≤ 1 clinically significant symptoms and no associated functional impairment (score of 1 on A-LIFE)

FDA Approval for Maintenance Treatment of Major Depressive Disorder

Medication Ages

Fluoxetine 8-17

Escitalopram 12-17

Maintenance Treatment for Adolescent Depression

Maintained Response (No Recurrence) at 52 Weeks38% Sertraline0% Placebo

Acute Phase Continuation Phase Maintenance PhaseSertraline

SertralineSertraline(n = 93) (n = 51)

(n = 13)

(n = 9)Placebo

Res

pond

ers

Res

pond

ers

12 weeks 24 Weeks 52 Weeks

Cheung et al, J Child Adolesc Psychopharmacology, 2008; 18:389-394

Treatment of Adolescent Depression Study (TADS)

439 adolescent outpatients with major depression

Randomized to twelve weeks Fluoxetine (10-40mg/day) CBT with fluoxetine (10-40mg/day) CBT alone Placebo

(Treatment for Adolescents with Depression Study (TADS) Team, JAMA 292:807-820, 2004)

Response Rates in TADS(CGI ≤ 2)

Week FLX + CBT FLX CBT PLB PLB/Open

12 73% 62% 48% 35%

18 85% 69% 65% 67%

36 86% 81% 81% 82%

(TADS Team, Arch Gen Psychiatry 2007;64:1132-1144; Kennard et al Am J Psychiatry 2009; 166:337-344)

Remission Rates in TADS

Remission Rate (CDRS-R≤28)Week FLX+CBT FLX CBT PBO PBO/Open12 39% 24% 19% 19%18 56% 37% 27% 34%36 60% 55% 64% 48%

• Greater the number of residual depressive symptoms at week 12, less likelihood of subsequent remission

(Kennard et al, J. Am Acad. Child Adolesc. Psychiatry 2009; 48:186-195) cont’d

TADS: Five Year Follow-Up

Higher recurrence among females (57%) than males (33%)Recovery: no clinically significant MDD symptoms for ≥ 8 weeksRecurrence: new episode of MDD following recovery

Curry J et al, Arch Gen Psychiatry. Published online November 1 2010. doi:10.1001/archgenpsychiatry.2010.150

Recovery Rate

Recurrence Rate

96%

47%

Antidepressants Plus CBT for Adolescent Depression

Meta-analysis of 5 randomized controlled studies FindingsNo significant additional benefit for CBT at short

term (12 weeks) or long term (28-36 weeks)Depressive symptomsSuicidalityClinical global improvement

Statistically significant benefit for impairment

Dubicka B et al. British J Psychiatry 2010; 197:433-440

Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) Trial

334 adolescents with major depression who failed to respond to 8 weeks of SSRI

Randomized to 12 weeks of: Different SSRI Different SSRI + CBT Switch to venlafaxine Switch to venlafaxine plus CBT

(Brent et al, JAMA 2008;299:901-913) cont’d

Clinical Response by Treatment Group(CGI≤2 and decrease CDRS-R≥50%)

% R

espo

nder

s

*p=.02

*SSRI

VLX

No CBT

CBT

(Brent et al, JAMA 2008;299:901-913)

Adverse Events

SSRIN=168

%

VenlafaxineN=166

%

No CBTN=168

%

CBTN=166

%≥1 Serious Adverse Event

11 11 8 14

Harm-relateda 19 22 19 22

≥ 1 Adverse Event 51 47 50 48

Suicide attempts 4 7 4 6

Skinb 2 8 4 5

aDefined as suicidal ideation, suicide attempt, or self-injurious behavior; bBy medication: χ²=6.69, p=.01;

Treatment Algorithm for Childhood Depression

Partial or no response


SSRI

Alternate SSRI

Stage 1

Stage 2

Stage 3Different class of antidepressant


Reassess, Treatment GuidanceStage 4

(Hughes et al, JAACAP 2007;46(6)667-686)

Clinical Use of Antidepressants

Medication Typical Starting Dose Target Dose (mg/day)Child Adolescent

Citalopram 5-10 10 20-40

Escitalopram 5 10 10-20

Fluoxetine 5-10 10 20-40

Paroxetine 5-10 10 20-40

Sertraline 25 50 100-200

Mirtazapine 15 15 30-45

Venlafaxine 37.5 37.5 150-225

Bupropion 50 bid 50 bid 100-200

Duloxetine 20 20 60-120

Adapted from: Wagner, K.D., Pliska, S.R (2009). Treatment of Child and Adolescent Disorders. In Schatzberg, A.F., & Nemeroff, C.B. (Eds.), The American Psychiatric Publishing Textbook of Psychopharmacology (1309-1372). Washington, DC: American Psychiatric Publishing, Inc.

Omega-3 Fatty Acids in Prepubertal Depression

28 children (ages 6-12 years) with first episode major depression randomized to Omega-3 (1000mg/day ; contained 400mg EPA and 200mg DHA) or placebo for 16 weeks

Groups Response Rate(>50% Reduction

in CDRS)

Remission (CDRS < 29)

Omega-3 70% 40%

Placebo 0% 0%

Nemets et al, Am J Psychiatry 2006; 163:1098-1100

Augmentation to SSRI for Treatment Resistant Depression

Atypical Antipsychotics Case series 10 adolescents with SSRI resistant

depression, 70% responded to augmentation with quetiapine

Antidepressants Bupropion, mirtazapine

Mood Stabilizer Lithium

Pathak S et al., J Child Adoles Psychopharmacology, 2005; 15:696-702.

Electroconvulsive Therapy

No controlled data

Retrospective study of 12 adolescents

33% had a 60% improvement in depressive symptoms

Hegeman JM et al, Tijdschr Psychiatr 2008; 50:23-31.

Repetitive Transcranial Magnetic Stimulation (rTMS)

9 adolescents with treatment resistant depression (failure of at least 1 course of psychotherapy and 2 courses of medications over 8 weeks each, at least one of them with fluoxetine (initially 20 mg/d and later 40 mg/d)

Open-label rTMS for 14 days (10Hz, 2-second trains given 20 min per day)

3 (33%) were responders (≥30% reductions in CDRS-R)

Bloch Y et al, J ECT 2008; 24:156-159.

Remission in Maternal Depression and Children’s Depression

Weissman MM et al. JAMA 2006; 295:1389-1398

Remission of Parental Depression

Garber J et al. Child Development 2011; 82:226-243

Offspring of Depressed Parent

Lifetime Prevalence of Adolescent Bipolar Disorder

National Comorbidity Survey – Adolescent Supplement Face-to-face study of 10,123 US adolescents, 13-18 yrs Modified Version of World Health Organization Composite

International Diagnostic Interview

Sex Age Total SevereImpairment

Female %

Male %

13-14 15-16 17-18 %

Bipolar I or II Disorder 303 2.6 1.9 3.1 4.3 2.9 2.6

Merikangas KR et al, JAACAP 2010; 49:980-989

Risk of Offspring With Bipolar Disorder

Number of Parents with Bipolar Disorder

No Parentn=2,239,553

One Parentn=11,995

Two Parentsn=83

Risk of Bipolar Disorderin Offspring

(Offspring n=1,080,030)

0.48%

(Offspring n=23,152)

4.4%

(Offspring n=146)

24.9%

• National register based cohort study in Denmark

Gottesman II et al. Arch Gen Psychiatry. 2010;67(3):252-257.

Comorbid Disorders Associated with Bipolar Disorder in Children and Adolescents

Soutullo CA et al. J Affect Disord. 2002;70(3):323-327; West SA et al. Biol Psychiatry. 1996;39(6):458-460; Geller B et al. J Child Adolesc Psychopharmacol. 2000;10(3):157-164; Wilens TE et al. J Am Acad Child Adolesc Psychiatry. 1999;38(6):680-685; Masi G et al. Can J Psychiatry. 2001;46(9):797-802; Birmaher B et al. J Clin Psychiatry. 2002;63(5):414-419; Jerrell JM et al. Bipolar Disord. 2004;6(4):299-304; Carlson GA et al. J Affect Disord. 1998;51(2):123-135; Kovacs M et al. J Am Acad Child Adolesc Psychiatry. 1995;34(6):715-723; Masi G et al. Biol Psychiatry. 2006;59(7):603-610. Sala R et al. J Clin Psychiatry 2010; 71:1344-1350

Estimated Prevalence (%)Attention deficit/hyperactivity disorder 49-87Substance abuse 8-47Anxiety disorder

Obsessive compulsive disorderPanicGeneralized anxiety disorderSocial anxietyPTSD

≥ Two anxiety disorders

4439-4419-2619-24401820

Oppositional defiant disorder 75Conduct disorder 69

Course of Bipolar I Disorder: Childhood to Adolescence

78 youth, ages 6-17 years with bipolar I disorder 4 year follow-up Results73% met bipolar I disorder criteriaOnly 6.4% euthymic

Wozniak J et al, High level of persistence of pediatric bipolar-I disorder from childhood onto adolescent...,Journal of Psychiatric Research (2010), doi:10.1016/j.jpsychires.2010.10.006

Eight Year Follow-up ofChildren With Bipolar I Disorder

Geller B et al. Arch Gen Psychiatry. 2008;65(10):1125-1133.

Recovery Rate88%

Baseline: N=115 children, mean age 11

Eight Year Follow-up ofChildren With Bipolar I Disorder


Relapse Rate73%

Course of Bipolar I Disorder: Childhood to Adulthood

115 children with bipolar I disorder

By young adulthood:• 44% had manic episodes• 20% had depressive episodes• 35% had substance use disorders


Medication % of Subjects % Weeks (Mean)Antimanic 63 48

Antipsychotic 51 46Lithium 32 21Anticonvulsant 42 32

Antidepressant 64 31ADHD Medication 77 50Anxiolytic 10 17Therapy

Individual 90 13Family 56 5Group 36 14

Geller B et al. Bipolar Disorders. 2010;12(2):164-171.

Treatments During Eight Year Follow-up

FDA Approved Medications for Pediatric Bipolar I Disorder, Mixed or Manic

Medication Age Range (y)Aripiprazole 10-17

Olanzapine 13-17

Risperidone 10-17

Quetiapine 10-17

Lithium 12-17

Negative* Controlled Multicenter Trials for Pediatric Bipolar I Disorder, Manic or Mixed

Medication Number of Subjects

Age Range(years)

Mean Dose(mg/day)

Study Duration(weeks)

Divalproex ER1 150 10-17 1286 (80 µg/L) 4

Oxcarbazepine2 116 7-18 1515 6

Topiramate3 56 6-17 278 4

*No statistically significant difference between medication and placebo on change in Young Mania Rating Scale from baseline to endpoint1Wagner KD et al. J Am Acad Child Adolesc Psychiatry. 2009;48(5):519-532; 2Wagner et al. Am J Psychiatry 2006;163(7)1-8; 3DelBello MP et al. J Am Acad Child Adolesc Psychiatry. 2005;44(6):539-547.

Controlled Trial of Flax Oil in Pediatric Bipolar Disorder

• 51 youths (ages 6-17 yr) with bipolar I or II disorder• Randomized to flax oil capsules (omega-3 fatty acids α-

linolenic acid) or olive oil placebo adjunctively or as monotherapy

• Doses titrated to 12 capsules/day over 16 weeks• Results:

No significant differences between flax oil and placebo groups on change in mania (YMRS), depression (CDRS-R) and Clinical Global Impression ratings

CDRS-R, Child Depression Rating Scale-Revised; YMRS, Young Mania Rating ScaleGracious BL et al. Bipolar Disord. 2010;12(2):142-154.

Risperidone Versus Divaproexin Pediatric Bipolar Disorder

Risperidone(n=32)

%

Divalproex(n=33)

%Increased appetite 25 31.3

Irritability/agitation 0 21.9*

Stomach discomfort 18.8 15.6

Sleepiness 15.6 12.5

Fatigue/tiredness 15.6 12.5

Insomnia 0 12.5

Weight gain 9.4 12.5

6 week double-blind randomized trial of risperidone (n=33) and divaproex (n=33)

*p<0.05 Pavuluri MN et al Bipolar Disorders 2010; 12:593-605.

**

Treatment of Early-Age Mania Study (TEAM Study)

279 youths, ages 6 to 15

Risperidonen=89

Lithiumn=90

Divalproexn=100

Geller B et al, Archives of General Psychiatry, in press

Dose / Blood Levels

Mean dose/level at endpoint (± SD) Risperidone: 2.6 ± 1.2 mg / day Lithium: 1.1 ± 0.3 mEq/L Divalproex: 114 ± 23 μg/mL

Adherence (pill count) ≥ 95%

Week 1 Week 2 Week 3 Week 4 Week 6 Week 8

Lithium levelMean ± SD; mEq/L

0.5 ± 0.2 0.7 ± 0.3 0.8 ± 0.3 0.9 ± 0.3 1.0 ± 0.3 0.9 ± 0.2

Valproate levelMean ± SD; μg/mL

68 ± 20 77 ± 16 86 ± 22 89 ± 19 96 ± 19 97 ± 27


Clinical Global Improvement at 8 weeks (Intent to treat: dropout = non-responder)

p < .001

Functional Outcome at Last Assessment

Risperidone > Lithium; OR = 3.02 (95% CI 1.4 – 6.3), p<.004Risperidone > Valproate; OR = 4.94 (95% CI 2.3 – 10.7), p<.001

Lithium = Valproate; OR = 1.64 (95% CI 0.7 – 3.6)Geller B et al, Archives of General Psychiatry, in press

Side Effects that Differed Among the 3 Medications

Risperidone Lithium Valproate

Baseline Weeks1-8 Baseline Weeks

1-8 Baseline Weeks1-8

Nausea 0% 16.9% 0% 35.7% 1.0% 23.7%

Vomiting 0% 7.9% 0% 21.4% 1.0% 11.3%

Abdominal Pain 9.0% 14.6% 6.0% 40.5% 11.3% 26.8%

Drowsiness 18.0% 50.6% 11.9% 26.2% 11.3% 35.1%

Frequent Urination 2.2% 6.7% 2.4% 28.6% 4.1% 14.4%

Dry Mouth 1.1% 10.1% 1.2% 21.4% 4.1% 7.2%

Excessive Thirst 3.4% 24.7% 3.6% 44.0% 4.1% 19.6%

Difficulty Arousing in AM 31.3% 34.8% 23.8% 29.8% 28.9% 63.9%

Rose highlighted cells differ, Dark > Light at p < .017Geller B et al, Archives of General Psychiatry, in press

Weight and Body Mass Index (BMI)

Weight gain greater on Risperidone (p < .001) Risperidone: 3.3 ± 1.7 kg Lithium: 1.4 ± 1.6 kg Divalproex: 1.7 ± 1.9 kg

Larger increase in BMI on Risperidone compared to Lithium (p<.001) and Valproate (p<.001)

Baseline BMI BMI Week 8 p

Risperidone 19.1 ± 4.5 20.4 ± 4.5 <.001

Lithium 19.6 ± 4.3 20.0 ± 4.4 NS

Valproate 19.4 ± 3.8 19.7 ± 4.1 <.001


Response Rates: Divalproex ER, TEAM and 5 second generation antipsychotic (SGA) trials

Placebo

Divalproex ER data from Wagner et al., J Am Acad Child Adol Psychiatry (2009)SGA data from Correll et al., Bipolar Disord (2010) Geller B et al, Archives of General Psychiatry, in press

FDA Approved Adjunctive Treatments

Aripiprazole and quetiapine as an adjunct to lithium or valproate for children (ages 10 years and older) for bipolar I disorder Approval for aripiprazole was based upon extrapolation

from adult data along with comparisons of aripiprazole pharmacokinetics in adults and pediatric patients. No aripiprazole study in pediatric patients Approval of quetiapine was established in one 3 week

monotherapy trial. No adjunctive trial in pediatric patients

Abilify prescribing information. 2009; Seroquel prescribing information. 2010

Treatment Duration

Minimum of 4 to 6 weeks for each medication trial

At therapeutic blood levels and/or adequate dose

Consider tapering medication after sustained remission of at least 12 to 24 consecutive months

(Kowatch et al., J Am Acad Child Adolesc Psychiatry 2005; 44:213-235)

Safety Issues Regarding Treatment of Pediatric Bipolar Disorder

Weight gain Diabetes Metabolic syndrome Cognitive dullness Hyperprolactinemia Polycystic ovarian syndrome Hypothyroidism Pancreatitis Abnormal involuntary movements Neuroleptic malignant syndrome

(Kowatch et al, J Am Acad Child Adolesc Psychiatry 2005; 44:214-235)

Cardiometabolic Risk of Atypical Antipsychotics

338 antipsychotic naïve youth, who received atypical antipsychotics over a 12 week period

Medication Mean Weight Gain (kg)Olanzapine 8.5Quetiapine 6.1Risperidone 5.3Aripiprazole 4.4Untreated Group 0.2

(Correll CU et al., JAMA. 2009;302(16):1765-1773)

Monitoring Youth Treated with Atypical Antipsychotics

Assessment Baseline Follow-up

Height, weight, BMI X Each visit

Fasting blood glucose and lipids

X At 3 months, then every 6 months

Liver function tests X At 3 months and annually

Electrolytes, blood count, renal funtion

X Annually

Prolactin Only if symptomatic

(Correll, J Am Acad Child Adolesc Psychiatry 2008;47:9-20) cont.

Monitoring Youth Treated with Atypical Antipsychotics

Assessment Baseline Follow-upBlood pressure and pulse X At 3 mo and annually

EKG XZiprasidone

During titration and maximum dose

ziprasidone

Parkinsonism, akathisia(Simpson Angus Rating Scale,

Extrapyramidal Rating Scale)

X During titration, at 3 mo and annually

Tardive dyskinesia (Abnormal Involuntary Movement Scale)

X At 3 mo and annually

(Correll, J Am Acad Child Adolesc Psychiatry 2008;47:9-20)

FDA: Suicidality and Antiepileptic Medications

FDA Conclusions

Twice the risk of suicidal behavior or ideation in patients treated with antiepileptic medication compared to placebo (.43% vs .22%) (NNH = 500)

Warning in Prescribing Label Antiepileptic medications increase risk of suicidal

thoughts and behaviors(FDA News 2008: FDA requires Warnings about Risk of Suicidal Thoughts and Behavior for Antiepileptic Medications)

Antiepileptic Drugs (AED) and Suicidal Attempts in Bipolar Disorder

• PharMetrics medical claims database• 47,918 patients with bipolar disorder• Results:

- No difference in suicide attempt rates for patients treated with AEDs or no AEDs

- In patients treated with AEDs, the rate of suicide attempts was significantly higher before treatment than after treatment

Gibbons RD et al. Arch Gen Psychiatry. 2009;66(12):1354-1360.

Open-label Lithium for AdolescentBipolar Depression

27 adolescent inpatients with bipolar I disorder, depressed Open label lithium (serum level 1.0-1.2mEq/L for 6 weeks

Results Response Rate 48%

(≥50% decrease CDRS-R) Remission Rate 30%

(CDRS-R ≤ 28, CGI-BP ≤ 2) Adverse effects: headache, nausea/vomiting, stomachache,

abdominal cramps

(Patel et al, J Am Acad Child Adolesc Psychiatry 2006 Mar;45(3):289-97)

Open-label Lamotrigine forAdolescent Bipolar Depression

20 adolescents with Bipolar I, II, or NOS disorder, depressed Open label lamotrigine (mean dose 132mg/day) as monotherapy

(n=13) or adjunctive treatment (n=7) for 8 weeks

Results Response rate

(CGI ≤ 2) 84%(≥ 50% decrease CDRS-R) 63%

Remission Rate 58%(CDRS-R ≤ 28, CGI ≤ 2)

Adverse effects: Headache, fatigue, nausea, sweating, difficulty sleeping

(Chang et al, J Am Acad Child Adolesc Psychiatry 2006:45(3):298-304 )

Double-Blind Placebo-Controlled Trial of Quetiapine for Bipolar Depression

32 adolescents with bipolar I disorder, depressed Randomized to quetiapine (mean dose 403mg/d) or placebo for 8

weeks.

Delbello et al. Bipolar Disorders 2009; 11:483-493

Child and Family-Focused Cognitive-Behavioral Therapy (CFF-CBT) for Pediatric Bipolar Disorder26 families of children with bipolar disorder. CFF-CBT adjunctive to pharmacotherapy showed improvement in manic symptoms

Main IngredientsR Establish RoutineA Affect regulationI “I can do it” (Positive thinking)

N “No negative thoughts” (Reframing thoughts)B “Be a good friend” (Positive social interaction)

O “Oh, how do we solve this problem” (Problem solving, Communication)W “Ways to find social support”

(West et al, J Can Acad Child Adolesc Psychiatry 2009; 18:239-246)

© 2003 Depression and Bipolar Support Alliance.

http://www.dbsalliance.org/

Medication Sheets



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Self-Assessment

1. Which one of the following identifies the MOST common adverse effects of psychostimulants?

a. Growth suppression and urticaria b. Insomnia and diminished appetite c. Insomnia and tics d. Psychosis and decreased appetite e. Psychosis and tics

2. When initiating treatment for a school-aged child, which of the following is the MOST effective single treatment for moderate to severe ADHD?

a. Academic accommodation b. Behavioral therapy c. Group therapy d. Pharmacotherapy e. Parent training

3. Which of the following is not approved by the FDA for the treatment of

ADHD? a. Atomoxetine b. Methylphenidate c. Risperidone d. Clonidine e. Guanfacine f. Lisdesamfetamine

4. Which antidepressant is FDA approved for the acute treatment of major depressive disorder in 9 year old children?

a. fluoxetine b. escitalopram c. venlafaxine d. sertraline

5. The number needed to treat (NNT) with antidepressants in pediatric major depression is?

a. 5 b. 10 c. 15 d. 20

6. Which medication is FDA approved for bipolar I disorder, mixed or manic in a 10 year old child?

a. lithium b. divalproex c. aripiprazole d. olanzapine

7. Which of the following selective serotonin reuptake inhibitors has been shown to be more efficacious than placebo for treating adults with autistic disorder?

a. Fluoxetine b. Fluvoxamine c. Sertraline d. Paroxetine

8. Which of the following atypical antipsychotics is most likely to lower the seizure threshold?

a. Olanzapine b. Ziprasidone c. Aripiprazole d. Clozapine

9. Which of the following hormones is being investigated as a potential treatment for the social impairment of autism?

a. Vasopressin. b. Thyroid Stimulating Hormone. c. Oxytocin. d. ACTH.

10. Which one of the medication below has no proven benefit for non-OCD

anxiety disorders in children? a. Fluvoxamine b. Fluoxetine c. Paroxetine d. Bupropion

11. For which of the following disorders is there the most support for

pharmacotherapy. a. Separation anxiety b. OCD

c. Social phobia d. PTSD

12. Controlled trials support the efficacy of antidepressants in all of the

following anxiety disorders but one: a. OCD b. Separation anxiety disorder. c. Social phobia d. Generalized anxiety disorder e. PTSD

1. b 2. d 3. c 4. a 5. b 6. c 7. b 8. d 9. c 10. d 11. b 12. e

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Pharmacology Children