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
Master Course 05 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.
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Master Course 05 Karen Wagner, M.D. Christopher McDougle, M.D. John Walkup, M.D.
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Agenda The materials contained in this packet were submitted and reviewed by the course /seminar director(s) and were correct at the time of print. Any changes to the material that were made after the review deadline are the responsibility of the course/seminar director(s).
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 The materials contained in this packet were submitted and reviewed by the course /seminar director(s) and were correct at the time of print. Any changes to the material that were made after the review deadline are the responsibility of the course/seminar director(s).
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
路
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 The materials contained in this packet were submitted and reviewed by the course /seminar director(s) and were correct at the time of print. Any changes to the material that were made after the review deadline are the responsibility of the course/seminar director(s).
Pharmacotherapy for Children & Adolescents with ADHD Christopher J. Kratochvil, M.D. Professor of Psychiatry & Pediatrics Assistant Vice Chancellor for Clinical Research University of Nebraska Medical Center Omaha, Nebraska
1
Disclosures: Past 12 months Consultant
Consultant for Quintiles. DSMB for Pfizer & Seaside.
Publishing
Oxford Press
Research funding Eli Lilly, Shire
2
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
3
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
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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.
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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.
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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.
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Pharmacotherapy for the Preschool Child
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Psychotropic Medications in Preschool Children with Medicaid: 1991-2001 (Zito, 2007)
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Psychopharmacological Treatment for Very Young Children: Contexts and Guidelines Gleason MM, Egger HL, Emslie GJ et al., JAACAP, 2007; 46(12):15321572
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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
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Psychopharmacological Tx Of Young Children Nonpharmacological treatments should be considered first – The psychotherapeutic interventions evidencebase for preschoolers is limited, but growing – Psychotherapeutic interventions should be tried first, and continue concomitantly with medication if medications are introduced
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Pharmacotherapy Algorithms At every treatment initiation point reassess diagnosis and clinical formulation Psychotherapeutic treatments are an integral part of every algorithm A discontinuation trial should follow each successful psychopharmacological treatment Avoid medications when therapy is likely to produce good results A system should be developed to track symptoms & impairment
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Psychopharmacological Treatment for Very Young Children: Contexts & Guidelines ADHD Algorithm 1. 2. 3. 4. 5.
Comprehensive diagnostic assessment Behavioral intervention, min. 8 weeks Methylphenidate Amphetamine Alpha agonist or atomoxetine
Gleason et al, JAACAP December 2007
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Pharmacotherapy (and other stuff) for Children & Adolescents with ADHD
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Common Questions asked by Patients and Parents
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Why didn’t kids have ADHD when I was growing up?
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ADHD
Historical Timeline Minimal Brain Damage
Hyperkinetic Reaction of Childhood (DSM-II) Attention Deficit Hyperactivity Disorder (DSM-III-R)
Efficacy of Amphetamine
1902 1930 1937 1950
1968
1980 1987 1994
Morbid Defect Minimal Brain Hyperactive Moral Dysfunction Child Syndrome Control Attention Deficit Disorder + or Hyperactivity (DSM-III)
Attention Deficit/Hyperactivity Disorder (DSM-IV)
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How is ADHD Diagnosed?
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How common is ADHD?
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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.
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What causes ADHD?
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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.
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Adults With ADHD Show Decreased Cerebral Metabolism Global and regional glucose metabolism by PET scan is reduced in adults who have been hyperactive since childhood Largest reductions in: – Premotor cortex – Superior prefrontal cortex
Normal
With ADHD
Copyright © 1990 Massachusetts Medical Society. All rights reserved. Zametkin AJ, et al. N Engl J Med 1990;323:1361-6.
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Anterior Cingulate (Cognitive Division) Fails to Activate in Attention-Deficit/Hyperactivity Disorder
Normal Controls Figure 3a. y = +21 mm
1 x 10-2
1 x 10-3
MGH-NMR Center & Harvard- MIT CITP
y = +21 mm
ADHD 1 x 10-2
1 x 10-3
Bush et al., 1999
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Why treat ADHD?
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Lifetime Impairments of ADHD
Disruptive behavior
Preschool School-age
Low self-esteem Smoking Substance use Crime Car accidents
Relationship failures Poor work history Chronic substance abuse and dependence Incarceration
Adolescent
Academic failure Poor socialization Self-esteem issues Injuries
Adult College-age
Academic failure Occupational failure Substance abuse
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Treatments Medication – Stimulant – Nonstimulant
Education – www.aacap.org – www.aap.org – www.nimh.org – www.parentsmedguide.org
Community support (www.chadd.org) Behavioral interventions School interventions
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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
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Multimodal Treatment of ADHD Study (MTA) Arch Gen Psych 1999;56:1073-86
579 children 7-9.9 y.o., 14 months of treatment Medication vs Intensive Behavioral vs Both vs Community Referral For ADHD symptoms, medication with & without behavioral therapy was superior to behavioral management alone Combined treatment not significantly better than medication alone for acute core ADHD symptoms
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Combined Treatment (Medication + Behavioral) Gold standard Lower doses of medication can be used Parents preferred combination treatment Benefits 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.
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Clinical Use of Stimulants Safety and efficacy data beginning in the 1930’s, with their role in treating children well established by the 1970’s. One of the best studied treatments in pediatric psychopharmacology One of the most robust responses in pediatric psychopharmacology
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AACAP ADHD Practice Parameters Search covered 5,000 references over the period from 19962006 AMA Council on Scientific Affairs – “Overall, ADHD is one of the best-researched disorders in medicine..” Pliszka, AACAP ADHD Practice Parameters JAACAP 2007
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AACAP ADHD Practice Parameters: Stimulants 65-75% clinical response in DBPC trials If 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
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What is the best way to dose the medication?
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Time Release Capsules IR beads
Protective membrane MPH Core Protective membrane Release control membrane
20 mg
ER beads
MPH Core
Drug release technology: “biphasic� release profile with combination of intermediate release (IR) and extended release (ER) MPH beads
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Oros速 Technology Orifice/exit port
Drug overcoat
Drug compartment #1
Ratecontrolled membrane
Drug compartment #2
Water
Water Push compartment
Before operation
During operation
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Methylphenidate Patch Concentrated drug-in-acrylic for delivery
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Methylphenidate Patch Applied to hip, for up to 9 hours Lag time – Package insert recommends application 2 hours before effect needed
Majority of subjects in Phase III clinical efficacy study had minimal to definite erythema, generally not resulting in discontinuation
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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
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Treatment Options—Stimulants Methylphenidate – 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)
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Side Effects of Stimulants Appetite suppression Insomnia Growth suppression Cardiovascular Rare: psychotic symptoms, mania
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Pharmacotherapy cont’d Non-stimulant Agents (only atomoxetine, guanfacine XR, and clonidine are FDAapproved for ADHD)
– – – – –
Atomoxetine (Strattera) Guanfacine XR (Intuniv) Clonidine XR (Kapvay) Bupropion (Wellbutrin) Desipramine (Norpramin)
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Indications for Atomoxetine (Strattera) FDA-approved for the treatment of children 6 years of age and older, adolescents, and adults Low substance abuse liability, so often seen as an option where there is a high risk of substance abuse or diversion May be useful for those with comorbid anxiety or comorbid Tourette’s
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Side Effects & Side Effect Management of Atomoxetine Stomach upset/vomiting Sedation Irritability Growth Liver Suicidality
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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 BID Maximum 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)
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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%)
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Dosing of Guanfacine XR Doses: 1mg, 2mg, 3mg, 4mg Titration is generally weekly Adverse effects may dictate rate of titration
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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 bedtime Should be discontinued slowly in decrements of no more than 0.1 mg every 3 to 7 days.
Total Daily Dose
Morning Dose
0.1 mg/day
Bedtime Dose 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
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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
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Education ParentsMedGuide.org CH.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
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Dosing Outside of School • Evenings • Weekends • Summers
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Are there other problems that frequently go along with ADHD?
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Comorbidity Often Complicates the Diagnosis and Treatment of ADHD ADHD alone
31% 40%
Tic Disorder
Oppositional Defiant Disorder
11%
Conduct Disorder
ADHD 14%
n=579
38%
Anxiety/Mood Disorders Jensen P, et al. Arch Gen Psychiatry 1999;56:1073-1086.
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Practice Parameters for the Assessment & Treatment of Children & Adolescents with ADHD ADHD frequently comorbid with other psychiatric disorders 54-84% will meet criteria for oppositional defiant disorder 15-19% will start to smoke or develop other substance disorders 25-35% will have learning or language problems Up to 1/3 will have anxiety disorders
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Comorbidities The rule, rather than the exception Can impact level of impairment Available pharmacotherapies are very effective. If several well-delivered interventions fail, reconsider a comorbidity If a previously effective medication becomes ineffective, consider first noncompliance, then potentially a newonset comorbidity
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Meta-Analysis: Tx of ADHD with Comorbid Tic Disorder Meta-analysis of 9 studies, 477 subjects D-amph, MPH, α-2 agonists, desipramine, ATM MPH, α-2 agonists, desipramine, and ATMX demonstrated efficacy in improving ADHD symptoms in children with comorbid tics α-2 agonists & ATMX improved comorbid tics MPH greatest & most immediate improvement of ADHD & didn’t worsen tics α-2 agonists best combined treatment Bloch et al, JAACAP September 2009
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Do children with ADHD outgrow ADHD?
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ADHD: Course of the Disorder Hyperactivity Impulsivity Inattention
Time
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ADHD: A Lifelong Disorder
Children with ADHD
75% persists into adolescence
Adolescents with ADHD
Prevalence in juvenile population 6%-9%
50% persists into adulthood
Adults with ADHD Prevalence in adult population 3%-5%
Wilens TE. Psychiatr Clin North Am. 2004;27:283-301.
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What about ADHD in young children?
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Growing use of Psychostimulants (Zito et al, JAMA, 2000)
Review of two medicaid programs and one managed care organization 1.23%, 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
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Preschool ADHD Treatment Study (PATS) 303 children, ages 3 to 5.5 years 165 were treated with MPH, starting at 1.25mg TID Mean 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 given Emotional outbursts, difficulty falling asleep, repetitive behaviors/thoughts, appetite decrease, and irritability were most frequently reported adverse effects Greenhill et al, JAACAP, 2006
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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
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Atomoxetine vs. Placebo for the Treatment of ADHD in 5- and 6-year-old Children Kratochvil 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.
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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 needed Despite benefits, the atomoxetine group overall remained significantly impaired at the end of the study
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I have heard that these medications effect growth, is that true?
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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
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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
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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
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What role does substance abuse play in ADHD?
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Earlier Initiation of Smoking with ADHD Smoking probability
0.6 0.5
ADHD n=128 Control n=109
0.4
6- to 17-year-old boys
0.3 0.2 0.1 0 0
2
4
6
8
10
12
14
16
18
20
22
24
P<0.003 Milberger S, et al. J Am Acad Child Adolesc Psychol. 1997;36:37-44.
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Pharmacotherapy of ADHD in the Context of Substance Abuse Extended-release guanfacine & clonidine Atomoxetine Bupropion* Modafinil* Lisdexamfetamine *Not FDA approved for ADHD
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I heard that there is a risk of heart problems with these medications, is that true?
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Cardiovascular Warnings Stimulants 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.
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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/pulse Monitor above during treatment No 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.
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Recent Cardiovascular Data: Journal of the American Medical Association American Journal of Psychiatry Pediatrics New England Journal of Medicine
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Stimulant Dosing No studies examining MPH or AMPH doses in children or adolescents above 60mg/d, or 72mg OROS On average linear dose-response relationship, with no evidence of a global â&#x20AC;&#x153;therapeuticâ&#x20AC;? window
Pliszka, AACAP ADHD Practice Parameters JAACAP 2007
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MPH Dosing Guidelines for Pediatric Patients U.S. FDA: maximum 60 mg/day for short-acting MPH and 72 mg/day for extended-release AACAP 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)
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Atomoxetine Dosing Target dose of 1.2 mg/kg/day Maximum dose 1.4 mg/kg/day, not to exceed 100mg Many of the early clinical trials dosed up to 1.8 mg/kg/day
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Off-Label Maximum Dose/Day Amphetamine 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
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Dosing Conclusions Current dose recommendations are appropriate for most patients No systematic advantage to increasing atomoxetine beyond current guidelines Continued 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
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Meta-Analysis: Tx of ADHD with Comorbid Tic Disorder Meta-analysis of 9 studies, 477 subjects D-amph, MPH, α-2 agonists, desipramine, ATMX, deprenyl MPH, α-2 agonists, desipramine, and ATMX demonstrated efficacy in improving ADHD symptoms in children with comorbid tics α-2 agonists & ATMX improved comorbid tics MPH greatest & most immediate improvement of ADHD & didn’t worsen tics α-2 agonists best combined treatment Bloch et al, JAACAP September 2009
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Clonidine: Alone & Combined with MPH for ADHD 16-week, randomized, DBPC trial of 122 children 7-12 y.o. with ADHD Clonidine vs MPH vs Clonidine/MPH vs PBO Conners 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
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Psychopharmacology of Autism Christopher J. McDougle, MD Director, Lurie Center for Autism Professor of Psychiatry and Pediatrics Massachusetts General Hospital and MassGeneral Hospital for Children Nancy Lurie Marks Professor Harvard Medical School 1
Disclosure of Financial Interests - Nothing to disclose
2
Off-Label Use Of Medication In this presentation, all discussion of use of medication refers to â&#x20AC;&#x153;off-labelâ&#x20AC;? use other than risperidone and aripiprazole for irritability in children and adolescents with autistic disorder
3
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.
4
Pervasive Developmental Disorders
Autistic Disorder Asperger’s Disorder Rett’s Disorder Childhood Disintegrative Disorder Pervasive Developmental Disorder Not Otherwise Specified
5
6
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe trantrums) Impaired social relatedness Sleep disturbance
7
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe trantrums) Impaired social relatedness Sleep disturbance
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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.
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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.
10
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.
11
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.
12
Crossover Phase: Other ABC Subscales ď Ž
ď Ž
Statistically significant worsening of parent-rated Social Withdrawal at highdose 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
13
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. 14
Categorical Response Placebo
Low
Asperger’s disorder/ PDD NOS (n=19)
6 (32%)
7 (37%)
Autism (n=47)
6 (13%)
13 (28%)
Medium 7 (37%)
High 6 (32%)
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. 15
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.
16
Treating Hyperactivity: Other Medications
Clonidine efficacious in 2 small placebocontrolled 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. MP et al. J Clin Psychiatry. 1992;53:77-82. 3Scahill L et al. J Child Adolesc Psychopharmacol. 2006;16(5):589-598 4Posey DJ et al. J Child Adolesc Psychopharmacol, 2006; 16(5):599-610. . 2Fankhauser
17
18
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe tantrums) Impaired social relatedness Sleep disturbance
19
Serotonin Reuptake Inhibitors (SRIs)
Rationale for studying SRIs in autism
Similarities to obsessive-compulsive disorder
Serotonin abnormalities in autism
20
SRIs in Autism for Repetitive Behavior
Clomipramine better than placebo and desipramine in children and young adults with autism1 Fluvoxamine better than placebo in ADULTS with 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. CJ et al. Arch Gen Psychiatry. 1996;53:1001-1008. 3McDougle CJ. Unpublished data. 4Hollander E et al. Neuropsychopharmacology. 2005; 30:582-589. 2McDougle
21
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. 22
ACTN Study of Fluoxetine in Autism: SOFIA
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 Network Autism Speaks, press release 2009
23
24
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe tantrums) Impaired social relatedness Sleep Disturbance
25
Typical Antipsychotics ď Ž
ď Ž
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.
26
Atypical Antipsychotics
Serotonin antagonism in addition to dopamine antagonism Lower risk of dyskinesias Individual drugs include
Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Paliperidone 27
Clozapine
Case reports only Can lower the seizure threshold Risk of agranulocytosis
Frequent blood draws necessary
28
29
Risperidone in Children With Autism and Serious Behavioral Problems RUPP 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)
30
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.
31
Acute Risperidone Trial: RUPP 100
(34/49) 80 Percent Responding
P < 0.001
69%
60 40
(6/52) 12%
20 0 Risperidone
Placebo
Response criteria: ≥25% improvement in the ABC-I score, and a rating of “much improved” or “very much improved” on the CGI-I ABC-I = Aberrant Behavior Checklist–Irritability. CGI-I = Clinical Global Impressions–Improvement. RUPP Autism Network. N Engl J Med. 2002;347:314-321.
32
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.
33
Baseline and Endpoint ABC Scores by Group ABC
Risperidone Baseline Endpoint
Placebo Baseline Endpoint
Irritability P < 0.001
26.2 (7.9)
11.3 (7.4)
25.5 (6.6)
21.9 (9.5)
Social Withdrawal P = 0.03/NS
16.4 (8.2)
8.9 (6.4)
16.1 (8.7)
12.0 (8.3)
Stereotypy P < 0.001
10.6 (4.9)
5.8 (4.6)
9.0 (4.4)
7.3 (4.8)
Hyperactivity P < 0.001
31.8 (9.6)
17.0 (9.7)
32.3 (8.5)
27.6 (10.6)
Inappropriate Speech P = 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.
34
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 sessions
RUPP Autism Network. J Am Acad Child Adolesc Psychiatry. 2009;48(2):1143-1154. 35
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. 36
37
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. 38
Quetiapine - Ziprasidone
No placebo controlled data with either drug Quetiapine: sedation Ziprasidone: less weight gain; potential ECG effects
39
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. 40
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, fixeddose (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. 41
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.
42
43
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.
44
Paliperidone for Irritability in Adolescents and Young Adults with Autism: Preliminary Results
Stigler et al. Preliminary data from poster presentation at 2010 APA.
45
46
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe tantrums) Impaired social relatedness Sleep disturbance
47
Medications Studied for Social Impairment in Autism
Not effective
Fenfluramine Naltrexone Lamotrigine Amantadine Risperidone Fluoxetine Citalopram 48
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.
49
Potential Targets of Pharmacotherapy 1. 2. 3.
4. 5.
Motor hyperactivity, inattention Interfering repetitive behavior Irritability (aggression, self-injury, severe trantrums) Impaired social relatedness Sleep disturbance
50
Medications for Sleep Disturbance
Melatonin Clonidine Trazodone Mirtazapine Hydroxyzine Doxepin Diphenhydramine and Benzodiazepines (paradoxical reaction, disinhibition) 51
Complementary and Alternative Medicine (CAM)
Secretin Gluten-free and Casein-free diet Oral Immunoglobulin Omega-3 fatty acids Vitamin B6/Magnesium
52
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
53
54
Questions??
55
Treatment of Children and Adolescents with Anxiety Disorders John T. Walkup, MD Division of Child and Adolescent Psychiatry Weill Cornell Medical College New York, NY
1
Disclosure: John T. Walkup, MD Consultant
Advisory Board
Speakerâ&#x20AC;&#x2122;s Bureau
AACAP Shire
Royalties
X X Drug and PBO X Drug X Drug and PBO
Abbott Lilly
Oxford Press Guilford Press
Research Contract
X
Pfizer
Tourette Syndrome Assoc.
Honorarium or Expenses Paid to Attend Meeting
X
X
X
X
2
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
3
Discussion of Off Label Use of Medications ď Ž
All medications use should be considered off label unless explicitly noted otherwise
4
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
5
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
6
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
7
Anxiety is not a great term
Other terms capture the experience better
Excessive interpersonal sensitivity Fear Apprehension Dread Excessive self-consciousness or shyness Worry
8
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
9
Assessment Strategies
Global scales with anxiety subscales
Child Behavior Checklist Behavioral Assessment System for Children
MASC SCARED (in your hand out)
10
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
11
The Treatment of OCD
12
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
13
Serotonin Reuptake Inhibitors FDA Approvals
Approved for OCD
Approved for Depression
Clomipramine > 10 yrs Fluvoxamine > 8 yrs Sertraline > 6 yrs Fluoxetine > OCD Fluoxetine > 12 yrs Escitalopram > 12 yrs
Approved for Non-OCD Anxiety
None
14
SRI Efficacy for Non-OCD Anxiety Disorders
SAD, GAD and SoP
SoP
Fluvoxamine – RUPP, 2001 Fluoxetine – Birmaher et al, 2003 CAMS – Walkup et al, 2009 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
15
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%
16
Other CAMS Outcomes Younger 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.
17
Other anxiety disorders ď Ž
Very limited data
18
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)
19
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
20
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
21
What to do about activation?
22
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
23
What to do about activation?
Switch
Second SSRI Non-activating antidepressant No evidence that any non-antidepressant will be useful
24
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
25
Medication Augmentation Strategies
March J, et al. Expert consensus Clomipramine guidelines: treatment of obsessive-compulsive disorder. J Clin Clonazepam Psychiatry. 1997;58(1-72 Neuroleptics IV Clomipramine Buspirone Add second SSRI Lithium Stimulants Psychotherapy augmentation – d-cycloserine ).
26
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
27
Strategies for Partial Response in OCD
Clomipramine Clonazepam Neuroleptics IV Clomipramine Buspirone Add second SSRI Lithium Stimulants Glutaminergic agents Others….. Psychotherapy augmentation – d-cycloserine
28
Enhancing Response
No disruption
Low disruption
Add new medication (augmentation)
Medium disruption
Adjust dose or add psychotherapy
Intensive psychotherapy
Large disruption
Change SRI
29
Clomipramine Augmentation
Low dose 10-50 mg/day
Higher doses
Pharmacokinetic and pharmacodynamic interaction Additive effects
Monitor side effects
HR, BP, EKG
30
Clonazepam
Not true augmentation Adjunctive treatment You pick the dose up to 4-6 mg/daily Long titration periods as per
31
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
32
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 Fluvoxamine
Sallee et al. 1997
33
Severe OCD
Check EKG etc Start with clomipramine, not SSRI Check levels and EKG
Check CMI:DCMI ratio
If>1 no problem If<1 consider adding low dose fluvoxamine
Add low dose fluvoxamine (Vendel et al. 1995)
Good levels consistent with good side effect management
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 ….
34
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
35
Add a Second SSRI
Logical Pharmacokinetic and pharmacodynamic interaction Most will tolerate, but some will not Use short half-life SSRIs
36
OCD Control
Switching SSRIs
Discontinue med
Start new med Time
37
Switching SSRIs â&#x20AC;&#x201C; Stopping old med too soon
OCD Control
Discontinue old med here
Start new med Time
38
Second drug offering improved benefit
OCD Control
Donâ&#x20AC;&#x2122;t cut old med dose
Dâ&#x20AC;&#x2122;C first med
Start new med Time
39
Second drug augments first drug but didn’t d’c first drug OCD Control
Don’t cut old med dose
Didn’t D’C first med
Start new med Time
40
Serotonergic Side Effect
Risk for Serotonergic Side Effects by Combining SSRIS Don’t cut old med dose
Didn’t D’C first med
Start new med Time
41
Lithium Augmentation
No controlled trials Excellent for comorbid depression Good third drug
42
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?
43
Stimulants
Good for SSRI-induced apathy Good for ADHD Good for mood disorders
44
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
45
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..
46
Glutaminergic Agents
Neuroprotective agents
Riluzole Memantine
Wait and see
47
Other Strategies
Pindolol Inositol
Herbal
Kava? But not St. John's wort, valerian, Sympathyl, or passionflower
48
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
49
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
50
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
51
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.
52
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
53
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!
54
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
55
CBT for Office Practice
The Anxiety Triad
Can impact all three by starting with any one
Thoughts, feelings, behavior
Thoughts – anxious bias to neutral event Feeling – discomfort and distress Behavior – avoidance
If you change the behavior the feelings and thoughts will follow.
56
CBT Resistant Symptoms ď Ž
Symptoms sustained by reinforcement patterns other than internal negative reinforcement
57
Types of Reinforcement Positive Reinforcement
Internally Reinforcing
Externally Reinforcing
Provides gratification
Attention and support
Negative Reinforcement
Relieves distress
Avoidance
58
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
59
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.
60
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.
61
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
62
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…
63
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 reevaluate including assessment of adherence
64
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
65
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??
66
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)
67
Summary
Medication and CBT effective Get used to “off label” prescribing Augmentation strategies need to be selected carefully Behavioral approaches can leverage psychopharmacology
68
Update on Pharmacological Treatment of Pediatric Mood Disorders Karen Dineen Wagner, MD, PhD Marie B. Gale Centennial Professor & Vice Chair Department of Psychiatry & Behavioral Sciences Director, Division of Child & Adolescent Psychiatry University of Texas Medical Branch Galveston, Texas
Financial Disclosure 9/2011 (Past 12 months)
ď&#x201A;§ Honoraria:
UMB Medica, Quantia Communications, CME LLC, American Psychiatric Association, Nevada Psychiatric Association, Slack Inc, Mercy, Hospital Universitario RamĂłn 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 Positive* Studies
Negative* Studies
Medication
Ages
Number of Studies
Citalopram
7-17
1
Sertraline
6-17
2 (a priori pooled analysis)**
Citalopram
13-18
1
Escitalopram
6-17
1
Mirtazapine
7-18 7-18
2
Nefazadone
7-17 12-17
2
Paroxetine
7-17 12-18 13-18
3
Venlafaxine
7-17 2 7-17 * 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)
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 Trials Depression 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=168 Open label Fluoxetine
ď&#x201A;§ 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 12 24 48 72
Remission Rates 18% 39% 65% 79%
Remission defined as: ≥ 3 weeks with ≤ 1 clinically significant symptoms and no associated functional impairment (score of 1 on A-LIFE) 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.
FDA Approval for Maintenance Treatment of Major Depressive Disorder
Medication
Ages
Fluoxetine
8-17
Escitalopram
12-17
Maintenance Treatment for Adolescent Depression
12 weeks
Sertraline (n = 51)
Maintenance Phase Sertraline (n = 13)
Responders
Sertraline (n = 93)
Continuation Phase
Responders
Acute Phase
24 Weeks
Placebo (n = 9) 52 Weeks
Maintained Response (No Recurrence) at 52 Weeks 38% Sertraline 0% Placebo 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
Week 12 18 36
Remission Rate (CDRS-R≤28) FLX CBT PBO FLX+CBT
39% 56% 60%
PBO/Open
24%
19%
19%
37%
27%
34%
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
Recovery Rate
96%
47% Recurrence Rate
Higher recurrence among females (57%) than males (33%) Recovery: no clinically significant MDD symptoms for ≥ 8 weeks Recurrence: new episode of MDD following recovery Curry J et al, Arch Gen Psychiatry. Published online November 1 2010. doi:10.1001/archgenpsychiatry.2010.150
Antidepressants Plus CBT for Adolescent Depression
Meta-analysis of 5 randomized controlled studies Findings No significant additional benefit for CBT at short term (12 weeks) or long term (28-36 weeks) Depressive symptoms Suicidality Clinical 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%) *
% Responders
SSRI VLX
No CBT CBT
*p=.02 (Brent et al, JAMA 2008;299:901-913)
Adverse Events SSRI N=168 %
Venlafaxine N=166 %
No CBT N=168 %
CBT N=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 bBy
as suicidal ideation, suicide attempt, or self-injurious behavior; medication: χ²=6.69, p=.01;
Treatment Algorithm for Childhood Depression SSRI
Stage 1
Partial or no response
Alternate SSRI
Stage 2
Partial or no response
Stage 3
Different class of antidepressant Partial or no response
Stage 4
Reassess, Treatment Guidance
(Hughes et al, JAACAP 2007;46(6)667-686)
Clinical Use of Antidepressants Medication
Typical Starting Dose
Target Dose (mg/day)
Child
Adolescent
5-10
10
20-40
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
Citalopram Escitalopram
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 ď&#x201A;§ 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
Remission (CDRS < 29)
Omega-3
Response Rate (>50% Reduction in CDRS) 70%
Placebo
0%
0%
Nemets et al, Am J Psychiatry 2006; 163:1098-1100
40%
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 Childrenâ&#x20AC;&#x2122;s Depression
Weissman MM et al. JAMA 2006; 295:1389-1398
Remission of Parental Depression
Offspring of Depressed Parent
Garber J et al. Child Development 2011; 82:226-243
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
Bipolar I or II Disorder
Age
Total
Female %
Male %
13-14
15-16
17-18
303
2.6
1.9
3.1
4.3
Merikangas KR et al, JAACAP 2010; 49:980-989
Severe Impairment %
2.9
2.6
Risk of Offspring With Bipolar Disorder
Number of Parents with Bipolar Disorder
Risk of Bipolar Disorder in Offspring
No Parent n=2,239,553
One Parent n=11,995
Two Parents n=83
(Offspring n=1,080,030)
(Offspring n=23,152)
(Offspring n=146)
0.48%
4.4%
24.9%
â&#x20AC;˘ 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 Estimated Prevalence (%) Attention deficit/hyperactivity disorder
49-87
Substance abuse
8-47
Anxiety disorder Obsessive compulsive disorder Panic Generalized anxiety disorder Social anxiety PTSD â&#x2030;Ľ Two anxiety disorders
44 39-44 19-26 19-24 40 18 20
Oppositional defiant disorder
75
Conduct disorder
69
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
Course of Bipolar I Disorder: Childhood to Adolescence
78 youth, ages 6-17 years with bipolar I disorder 4 year follow-up Results 73% met bipolar I disorder criteria Only 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 of Children With Bipolar I Disorder Baseline: N=115 children, mean age 11
Recovery Rate 88%
Geller B et al. Arch Gen Psychiatry. 2008;65(10):1125-1133.
Eight Year Follow-up of Children With Bipolar I Disorder
Relapse Rate 73%
Geller B et al. Arch Gen Psychiatry. 2008;65(10):1125-1133.
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.
Treatments During Eight Year Follow-up Medication
% of Subjects
% Weeks (Mean)
63
48
Antipsychotic
51
46
Lithium
32
21
Anticonvulsant
42
32
Antidepressant
64
31
ADHD Medication
77
50
Anxiolytic
10
17
Individual
90
13
Family
56
5
Group
36
14
Antimanic
Therapy
Geller B et al. Bipolar Disorders. 2010;12(2):164-171.
FDA Approved Medications for Pediatric Bipolar I Disorder, Mixed or Manic Medication Aripiprazole
Age Range (y) 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 Âľg/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 endpoint 1Wagner 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 αlinolenic 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 Scale Gracious BL et al. Bipolar Disord. 2010;12(2):142-154.
Risperidone Versus Divaproex in Pediatric Bipolar Disorder 6 week double-blind randomized trial of risperidone (n=33) and divaproex (n=33)
* *
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
0
12.5
9.4
12.5
Insomnia Weight gain *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
Risperidone n=89
Geller B et al, Archives of General Psychiatry, in press
Lithium n=90
Divalproex n=100
Dose / Blood Levels
Lithium level
Week 1
Week 2
Week 3
Week 4
Week 6
Week 8
0.5 ± 0.2
0.7 ± 0.3
0.8 ± 0.3
0.9 ± 0.3
1.0 ± 0.3
0.9 ± 0.2
68 ± 20
77 ± 16
86 ± 22
89 ± 19
96 ± 19
97 ± 27
Mean ± SD; mEq/L
Valproate level Mean ± SD; μg/mL
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% 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<.004 Risperidone > 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
Weeks 1-8
Baseline
Weeks 1-8
Baseline
Weeks 1-8
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 < .017 Geller 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 ď&#x201A;§ Aripiprazole and quetiapine as an adjunct to lithium or valproate for children (ages 10 years and older) for bipolar I disorder ď&#x201A;§ 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 ď&#x201A;§ 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
8.5
Quetiapine
6.1
Risperidone
5.3
Aripiprazole
4.4
Untreated 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 Blood pressure and pulse EKG
Parkinsonism, akathisia
Baseline X
At 3 mo and annually
X Ziprasidone
During titration and maximum dose ziprasidone
X
During titration, at 3 mo and annually
X
At 3 mo and annually
(Simpson Angus Rating Scale, Extrapyramidal Rating Scale)
Tardive dyskinesia
Follow-up
(Abnormal Involuntary Movement Scale) (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 Adolescent Bipolar 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 for Adolescent 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) (≥ 50% decrease CDRS-R)
Remission Rate
84% 63% 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 ď&#x201A;§ 32 adolescents with bipolar I disorder, depressed ď&#x201A;§ 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 Disorder 26 families of children with bipolar disorder. CFF-CBT adjunctive to pharmacotherapy showed improvement in manic symptoms Main Ingredients
R A I N B O W
Establish Routine Affect regulation “I can do it” (Positive thinking) “No negative thoughts” (Reframing thoughts) “Be a good friend” (Positive social interaction) “Oh, how do we solve this problem” (Problem solving, Communication) “Ways to find social support”
(West et al, J Can Acad Child Adolesc Psychiatry 2009; 18:239-246)
http://www.dbsalliance.org/ Š 2003 Depression and Bipolar Support Alliance.
Medication Sheets
References The materials contained in this packet were submitted and reviewed by the course /seminar director(s) and were correct at the time of print. Any changes to the material that were made after the review deadline are the responsibility of the course/seminar director(s).
1. Brent D, Emslie G, Clarke G, Wagner KD, Asarnow JR, Keller M, Vitiello B, Ritz L, Iyengar S, Abebe K, Birmaher B, Ryan N, Kennard B, Hughes C, DeBar L, McCracken J, Strober M, Suddath R, Spirito A, Leonard H, Melhem N, Porta G, Onorato M, Zelazny J: Switching to another SSRI or to Venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: The TORDIA randomized controlled trial. JAMA. 2008; 299:901. 2. Correll CU: Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry. 2008; 47:9. 3. Correll CU, Carlson HE: Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry. 2006; 45:771. 4. Gleason MM, Egger HL, Emslie GJ, Greenhill LL, Kowatch RA, Lieberman AF, Luby JL, Owens J, Scahill LD, Scheeringa MS, Stafford B, Wise B, Zeanah CH: Psychopharmacological treatment for very young children: Contexts and guidelines. J Am Acad Child Adolesc Psychiatry. 2007; 46:1532. 5. *Greenhill L, Kollins S, Abikoff H, McCracken J, Riddle M, Swanson J, McGough J, Wigal S, Wigal T, Vitiello B, Skrobala A, Posner K, Ghuman J, Cunningham C, Davies M, Chuang S, Cooper T: Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc Psychiatry. 2006; 45:1284. 6. Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH, Aman MG: A placebo-controlled, fixed-dose study of aripiprazole in children and
adolescents with irritability associated with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2009; 48:1110. 7. Pappadopulos E, MacIntyre JC, Crismon ML, Findling RL, Malone RP, Derivan A, Schooler N, Sikich L, Greenhill L, Schur SB, Felton CJ, Kranzler H, Rube DM, Sverd J, Finnerty M, Ketner S, Siennick SE, Jensen PS: Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry 2003; 42:145. 8. Pliszka S, AACAP Work Group on Quality Issues: Practice parameter for the assessment and treatment of children and adolescents with attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007; 46:894. 9. Research Units on Pediatric Psychopharmacology Autism Network: Risperidone in children with autism and serious behavioral problems. N Engl J of Med. 2002; 347:314. 10. Schelleman H, Bilker WB, Strom BL, Kimmel SE, Newcomb C, Guevara JP, Daniel GW, CZiraky MJ, Hennessy S: Cardiovascular Events and Death in Children Exposed and Unexposed to ADHD Agents. Pediatrics. 2011; 127:1102. 11. *The MTA Cooperative Group: A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999; 56:1073. 12. *The Pediatric OCD Treatment Study (POTS) Team: Cognitive-behavioral therapy, sertraline, and their combination for children and adolescents with
obsessive-compulsive disorder: The pediatric OCD treatment study (POTS) randomized controlled trial. JAMA. 2004; 292:1969. 13. *The Research Unit on Pediatric Psychopharmacology Anxiety Study Group: Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med. 2001; 344:1279. 14. *Treatment for Adolescents with Depression Study (TADS) Team: Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for adolescents with depression study (TADS) randomized controlled trial. JAMA. 2004; 292:807.
Self-Assessment The materials contained in this packet were submitted and reviewed by the course /seminar director(s) and were correct at the time of print. Any changes to the material that were made after the review deadline are the responsibility of the course/seminar director(s).
1. Which one of the following identifies the MOST common adverse effects of psychostimulants? a. b. c. d. e.
Growth suppression and urticaria Insomnia and diminished appetite Insomnia and tics Psychosis and decreased appetite 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. b. c. d. e.
Academic accommodation Behavioral therapy Group therapy Pharmacotherapy 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. b. c. d.
lithium divalproex aripiprazole 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