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Masters course psych pharma children
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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
1. Coffee and tea are available at Java City, on Level 2 near Exhibit Hall A. You MUST present your beverage voucher in order to redeem a beverage.
2. Please vacate the classroom promptly at the conclusion of the course. If you
must speak to the Course Director or Faculty, please do so outside of the room. Audiovisual and hotel personnel must have time to set the room for the next
session or function.
3. Please remember to complete your course evaluation at www.apaeducation.org.
Thank you for enrolling in the CME courses.
Master Course 05
Karen Wagner, M.D.
Christopher McDougle, M.D.
John Walkup, M.D.
Evaluation Instructions
To complete your course evaluation and claim AMA PRA Category 1 CME Credits™, follow the directions below:
1) Go to www.apaeducation.org 2) Click the link in the left navigation area titled “Enter CME Code for Credit”
3) Enter your user ID and password when prompted. If you pre-registered for the
meeting, you received this information via email from [email protected]. OR If you were a last-minute registrant or you have never participated in an APA-sponsored CME activity, please click the link “Click here to create a new account.” Make a note of your user ID and password.
4) Enter your CME code from the course packet and click Submit.
5) Verify that the course title matches the title on your course packet. 6) Click Proceed to Course Enrollment. 7) Click on “Enrollment Complete – Return to Student Home Page.” 8) Click the launch icon to the right of the course title.
9) Complete the evaluation and click the Submit button. Your course will then be
marked as Completed Satisfactorily and moved to your My Transcript page. 10) Click the My Transcript link in the left navigation menu. 11) Click the link “Completed Satisfactorily” to the right of the course title. 12) Choose the type of certificate you wish to use. Change the credits claimed if
necessary.
13) Click Claim and Print to generate your certificate.
�e materials contained in this packet were submittedand reviewed by the course /seminar director(s) andwere correct at the time of print. Any changes to the
material that were made a�er the review deadlineare the responsibility of the course/seminar director(s).
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.
�e materials contained in this packet were submittedand reviewed by the course /seminar director(s) andwere correct at the time of print. Any changes to the
material that were made a�er the review deadlineare the responsibility of the course/seminar director(s).
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
�e materials contained in this packet were submittedand reviewed by the course /seminar director(s) andwere correct at the time of print. Any changes to the
material that were made a�er the review deadlineare the responsibility of the course/seminar director(s).
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
Principles on the Use of Psychotropic Medication in Children and Adolescents
(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
Principles on the Use of Psychotropic Medication in Children and Adolescents
(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
Pliszka, AACAP ADHD Practice Parameters JAACAP 2007
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
Pliszka, AACAP ADHD Practice Parameters JAACAP 2007
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
Pliszka, AACAP ADHD Practice Parameters JAACAP 2007
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
Potential Targets of Pharmacotherapy
1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury, severe
trantrums) 4. Impaired social relatedness5. Sleep disturbance
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
RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.
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)
RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.
16
MPH Summary
35/72 subjects (49%) responded to MPH
13/72 (18%) exposed to MPH dropped out due to adverse events
RUPP Autism Network. Arch Gen Psychiatry 2005; 62:1266-1274.
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
Potential Targets of Pharmacotherapy
1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury, severe
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
Potential Targets of Pharmacotherapy
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
Potential Targets of Pharmacotherapy
1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury, severe
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
Potential Targets of Pharmacotherapy
1. Motor hyperactivity, inattention2. Interfering repetitive behavior3. Irritability (aggression, self-injury, severe
trantrums) 4. Impaired social relatedness5. Sleep disturbance
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
What to do about activation?
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
What to do about activation?
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
Don’t cut old med dose
Start new med
Didn’t D’C first med
Time
OCD
Con
trol
41
Risk for Serotonergic Side Effects by Combining SSRIS
Don’t cut old med dose
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
CBT for Office Practice
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
CBT for Office Practice
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
Partial or no response
SSRI
Alternate SSRI
Stage 1
Stage 2
Stage 3Different class of antidepressant
Partial or no response
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
Geller B et al. Arch Gen Psychiatry. 2008;65(10):1125-1133.
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
Geller B et al. Arch Gen Psychiatry. 2008;65(10):1125-1133.
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
Geller B et al, Archives of General Psychiatry, in press
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
Geller B et al, Archives of General Psychiatry, in press
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
�e materials contained in this packet were submittedand reviewed by the course /seminar director(s) andwere correct at the time of print. Any changes to the
material that were made a�er the review deadlineare the responsibility of the course/seminar director(s).
References
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�e materials contained in this packet were submittedand reviewed by the course /seminar director(s) andwere correct at the time of print. Any changes to the
material that were made a�er the review deadlineare the responsibility of the course/seminar director(s).
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