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

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

Objectives from ADMSEP Psychiatry Learning Objectives Taskforce, 2007 By completion of the clerkship/medical school, the student will be able to: Slide 2

ADMSEP Objectives—con’t 1. Discuss the common, currently available psychotropic medications with regard to clinical indications and contraindications, presumed mechanism of action and relevant pharmacodynamics, common and serious adverse effects, pharmacokinetics, evidence for efficacy, cost, risk of drug-drug interactions and drug-disease interactions, and issues relevant to use in special populations (e.g., pregnancy and lactation, childhood and adolescence, the elderly, persons using herbal and over-the-counter treatments). 2. Propose selected psychotropic pharmacotherapy for designated patients and provide clinical reasoning that includes discussion of factors influencing treatment selection (e.g.,patient-specific and drug-specific variables, scientific evidence). Slide 2

ADMSEP Objectives—con’t 3. Discuss the factors relevant to implementing, monitoring and discontinuing psychotropic pharmacotherapy including drug dosing, treatment duration, and adherence, and make management recommendations for dealing with an unsuccessful treatment trial (e.g., lack of efficacy, intolerability). 4. Counsel patients about psychotropic pharmacotherapy including risks and benefits of recommended treatment, treatment alternatives, and no treatment 5. Identify and discuss resources to maintain an up-to-date knowledge of psychotropic pharmacotherapy Slide 2

ADMSEP Objectives—con’t 6. Discuss special issues and concerns related to specific psychotropic drug classes including metabolic, hematologic, hepatic, etc. Slide 2

Objectives for MS II At the end of this lecture, the student will: Be able to articulate the basics of using psychotropics in children and adolescents Be able to name the basic drugs used for children and adolescents and their clinical indications

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

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

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

Epidemiology of Common Child and Adolescent Psychiatric Disorders ADHD: Prevalence ADHD is one of the most common mental disorders in childhood Conservative estimates of 4-7% in grade school children 4.4 million, 7.8%, of 4-17 y.o. U.S. children have a history of ADHD by parent report (CDC, MMWR Weekly 54:842-847, 2005)

Pediatric Depression Epidemiology Distribution by Sex 0.3% of pre-schoolers 2% of school-aged children 5% of adolescents 20-25% lifetime prevalence by the end of adolescence (Kessler et al, Biological Psychiatry 2001;49:1002-1014.) Distribution by Sex Approximately equal before puberty 2:1 female to male ratio after puberty

Child & Adolescent Anxiety Disorders Among the most prevalent of child and adolescent psychiatric disorders 15.4% children in pediatric primary care sample of 300 7-11y.o. met criteria for an anxiety disorder during a 1-year period (Benjamin et al 1990) Of 792 eleven-year-olds, 3.5% separation anxiety d/o, 2.4% simple phobia, 2.9% overanxious d/o, 1% social phobia (Anderson et al 1987)

Autism Spectrum Disorders Autistic Disorder Occurs in 4 out of 10,000 children Distributed equally among all socioeconomic levels Male to Female ratio 3:1 (Females affected more severely, with greater neurological impairment) Asperger’s Syndrome More common in boys than girls 10:1 Not associated with socioeconomic status or parental education Prevalence was thought to be 0.6-4 per 10,000 A Swedish survey estimated 10-26 per 10,000

Attention-Deficit/Hyperactivity Disorder

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

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

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

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

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

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

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

Optimizing Response to Stimulants IR = 4 hrs Ritalin LA = 8 hrs Metadate CD = 6-8 hrs Concerta/Adderall XR = 10-12 hrs In general, use extended-release formulations Give first dose as early as possible in AM Increase dose to ensure maximum benefit achieved Sculpt the dose: examples of potential combinations Give immediate release TID Give Metadate CD or Ritalin LA BID Give IR early AM and Concerta/Adderall XR around noon Give Concerta/Adderall XR early and IR around 6 PM Greenhill LL, Pliszka S, Dulcan MK, et al; American Academy of Child and Adolescent Psychiatry. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41(suppl 2):26S-49S. Silver L. Update on ADHD medications. LD Online [serial online]. Available at: http://www.ldonline.org/ld_indepth/add_adhd/adhd_medications_update.html. Accessed October 16, 2003. Greenhill LL, et al. J Am Acad Child Adolesc Psychiatry 2002;41(suppl 2):26S-49S

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

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

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

Adverse Effects of Atomoxetine & Management Dyspepsia Sedation Irritability Hepatic Suicidality

Preschoolers with ADHD Treatment Study (PATS) Aim- To test the efficacy and tolerability of methylphenidate for preschool children N= 165 3-5 years old 12 weeks Randomized, placebo-controlled. Cross-over with 4 fixed doses plus PBO (1 week each), followed by a 4-week parallel group, and a 10-month naturalistic maintenance phase. Greenhill, Kollins, Abikoff et al, J Am Acad Child Adolesc Psychiatry, 2006, 45(11):1284-1293

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

Depression

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

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

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

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

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

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

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

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

The Treatment of Resistant Depression in Adolescents Study (TORDIA) Aim: to compare the effectiveness of an alternative antidepressants (SSRIs or venlafaxine), alone and in combination with CBT, in adolescents with depression who failed an adequate initial SSRI trial 12 weeks of Switch to 2nd, different SSRI (paroxetine, citalopram, or fluoxetine) Switch to a different SSRI + CBT Switch to venlafaxine Switch to venlafaxine + CBT N= 326 12-18 years old 12 weeks of acute treatment followed by a 12 week continuation Brent, Emslie, Clark et al, JAMA 2008, 299:901-913.

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

Pediatric Anxiety Disorders

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

Child and Adolescent Anxiety Multimodal Study (CAMS) Aim: to compare sertraline and CBT, alone and in combination, to PBO. N=488 subjects with separation anxiety disorder, generalized anxiety disorder, or social phobia Age: 7-17 years Duration- 12-week trial Walkup et al, NEJM, 359(26): 2753-2766: 2008

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

Research Units of Pediatric Psychopharmacology (RUPP) Fluvoxamine Study Fluvoxamine (RUPP studies 2001, 2002) 50-300 mg, 8 wks, n=128 in 6-17 yrs Generalized Anxiety Disorder, Separation Anxiety Disorder, or Social Phobia persisting after 3 wks supportive psychotherapy Response Rates= FLVX 76% v 29% placebo Adverse effects= stomachache, motor activation 28% v 12% placebo

Research Units of Pediatric Psychopharmacology (RUPP) Fluvoxamine Study 6 mo open label extension-94% continued remission Fluvox non-responders-> Fluoxetine (n=14) 20-40 mg 71% response by clinician rating and PARS Higher level of depression, SP and severity of illness- less drug efficacy; ES=1.1 largely because of low placebo response Take home message: If no response from first SSRI, try a second one

The Pediatric Obsessive-Compulsive Disorder Treatment Study (POTS) Aim- to test efficacy of sertraline and CBT, alone and in combination in children with OCD, compared to PBO OCD in Children and Adolescents: A Cognitive Behavioral Approach, JS March & K Mulle, Guilford Press N= 112 7-17 years old 12 weeks The Pediatric OCD Treatment Study (POTS) Team, JAMA 2004 292(16): pp 1969-76

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

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

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

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

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

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

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

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

Answers A D

End of Lecture