Pharmacological Management of Attention Deficit Hyperactivity Disorder & Disruptive Behavior Disorders

1. Pharmacological Management of Attention Deficit Hyperactivity Disorder & Disruptive Behavior Disorders Annual Pharmacological Conference for Advanced Practice Nurses Terri Mathews, Ph.D., APRN-NP, BCBA-D July 21, 2011

2. Attention Deficit Hyperactivity Disorder (ADHD) • Incidence – Approx. 3-8% of children • 60% of children will continue to have diagnosis in teenage years and adulthood • Male: female ratio 4:1 • Symptoms often occur in children as young as three year of age • Comorbidities with ADHD • 54-80% ODD/Conduct disorder • 25 – 35% Language Disorder • 33% Anxiety Disorders • 0-33% Mood disorders • 16% - Met criteria for Mania

3. Definition • Deficits in Hyperactivity, Impulsivity and Regulating Attention • Deficits in executive functioning • Processes that maintain appropriate problem solving to set a future goal • Impaired response inhibition • Impaired vigilance • Impaired working memory • Poor planning capacity

4. Etiology • Genetic - Heritability - 76% • Seven genes have shown significant association with ADHD • Non - Genetic • Exposure to infection • Prenatal toxic exposure • Perinatal stress • Low birth weight • Prematurity • Traumatic brain injury • Very severe early neglect

5. ADHD – Diagnosis Inattention • Fails to pay close attention to details/makes careless mistakes • Does not listen when spoken directly to • Does not follow through on instructions • Difficulty organizing tasks • Avoids, dislikes and does not engage in tasks that require sustained mental efforts • Loses things necessary for tasks or activities • Easily distracted by external stimuli • Forgetful in Daily activities

6. Hyperactivity – • Fidgets – squirms in seat • Leaves seat in classroom excessively • Runs or climbs excessively • Difficulty engaging or playing in leisure activity quietly • Often “on the go” or “driven by a motor” • Talks excessively • Impulsivity - • Blurts outs answers before questions complete • Difficulty waiting turn • Interrupts or Intrudes on others

7. DSM – IV –TR Diagnosis At least some impairment before seven years of age Symptoms present in at least two settings Clinically significant impairment in social, academic or occupational functioning Not other accounted for by a mental condition

8. Assessment • Semi-structured interview • Rating Scales from 2 environments • CBCL • Connor’s • Vanderbilt ADHD • DSM-IV-TR ADHD scales • Sampling of school work • Accuracy • Completeness • Time involved • Check desk for preparation • Observation of amount of time on-task

9. Treatment Recommendations • Comprehensive Treatment Plan • Parental and Child Psychoeducation • Psychotherapy • Parent Management Training • Medication Management • Careful evaluation for cardiac risk factors • Monitor for Side Effects • Evaluation

10. Pharmacological Management • Before Starting • Complete History and Physical • Consider Cardiovascular Health History • If history of arrhythmias, structural heart defect, or family history of arrhythmias or sudden death, pediatric cardiology consult and EKG prior to initiation. • Height and Weight on All Patients • Consideration of Substance Abuse • Stigma • Family Lifestyle (Adherence)

11. Stimulant Medications • Stimulant medications are the most studied, most commonly used first-line agents for ADHD treatment • Stimulant medications improve: • Core symptoms: inattention, impulsivity, hyperactivity • Associated symptoms: cognition, on-task behavior, academic performance, social function, defiance, and aggression • Effective in preschoolers, school-age children, adolescents and adults

12. Stimulant Medications • Two primary classes of stimulants • Amphetamines and methylphenidate (MPH) • Response rate for any one particular stimulant is approx. 70% • No predictors of response have been identified • All stimulants are generally of comparable efficacy • There is significant individual variability in response to a particular stimulant

13. Stimulant Medications MPH-based and amphetamine-based stimulants have different effects at the neurotransmitter level • MPH • Inhibits the activity of the presynaptic dopamine transporter protein involved in the reuptake of dopamine from the synaptic cleft • Amphetamines • Blocks the reuptake of dopamine and norepinephrine through inhibition of the dopamine transporter protein • Increases retrograde release of catecholamines (dopamine and norepinephrine) through the transporter

14. Methylphenidate Effect

15. Amphetamine based effect

16. Preparations • methylphenidate (Ritalin, Methylin, Metadate) • Long acting preparations: Ritalin-SR, Ritalin LA, Methylin-ER, Metadate-ER, Metadate-CD, Concerta, Daytrana • Methylin comes in an liquid and chewable tablet form • Daytrana delivers MPH via a transdermal patch • dexmethylphenidate (Focalin) • Long acting preparation: Focalin XR

17. Amphetamine based mixed amphetamine salts products (Adderall) • Long acting preparation: Adderall XR lisdexamfetamine dimesylate (Vyvanse) • Prodrug of dextroamphetamine dextroamphetamine (Dexedrine, Dextrostat) • Long acting preparation: Dexedrine spansules

18. Long-Acting Stimulant Preparations

19. Side Effects • Most side effects are transient and dose dependent • Common side effects include: insomnia, decreased appetite, mild increase in heart rate and BP, weight loss, headache, nausea • Rare side effects include: behavioral rebound, psychosis, anxiety or depression • Dexmethylphenidate (Focalin) may have fewer side effects than MPH

20. Management of Side Effects • Anorexia – • Small frequent snacks • Highly dense calories • Instant Carnation breakfast • Assure good breakfast before am dose • Cyproheptadine 2- 4 mg tid • Insomnia • Good bedtime hygiene • Decrease late afternoon stimulant • Melatonin 1-6 mg at HS

21. Dosing • Start low and titrate up slowly • Each patient has a unique-response curve • FDA Maximum doses – • Methylphenidate – 60 mg • Daytrana – 30 mg • Concerta – 72 mg • Focalin XR – 30mg • Adderall XR – 40 mg • Vyvanse – 70 mg

22. Contraindications to Stimulant Use Glaucoma Hyperthyroidism Overt cardiovascular disease Psychosis Substance abuse disorders (abuse potential is very low with medical supervision) Uncontrolled hypertension Concomitant prescription with MOAIs

23. Selective Norepinephrine Reuptake Inhibitor Atomoxetine (Strattera) – • First non-stimulant, FDA approved medication for treatment of ADHD in children, adolescents and adults (November, 2002) • Highly selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex • Preferentially binds to areas of known high distribution of noradrenergic neurons in the fronto-cortical subsystem • Increases noradrenergic transmission • Important for attention, learning, memory and adaptive responses

24. Indications • Effective in reducing scores on ADHD – RS from baseline to endpoint • As effective as immediate release stimulants but not as effective as osmotically-release MPH or amphetamine salts • May be first line of treatment for those with history or concern of substance abuse, tics & anxiety • Comorbid conditions • May show effectiveness with comorbid anxiety (Sumner, 2005) & possibly Oppositional Defiant Disorder (Dittman et al., 2011)

25. Selective Norepinephrine Reuptake Inhibitor Atomoxetine (Strattera) Safety data • Diastolic BP and heart rate increase but not clinically significant • No significant lab or EKG changes • No exacerbation of tics or anxiety • No abuse potential • Monitor for liver dysfunction • Drug interactions with paroxetine and to a less extent fluoxetine *** Black box warning – may increase suicidal thoughts

26. Atomoxetine • Side Effects • Headache • Abdominal pain • Anorexia • Nausea up to several weeks • Vomiting • Sedation and fatigue • Irritability • Dizziness

27. Atomoxetine • Dosing • Once or twice daily (evenly divided doses) • 0.5 mg/kg and titrate to target dose of 1.2 mg/kg after minimum 3 days • maximum dose of 1.4 mg/kg • May discontinue without tapering • Several weeks before effective – can take up to 6-8 weeks

28. Alpha-2 adrenergic agonists • guanfacine (Tenex and Intuniv) • clonidine (Catapres) • Reduces brainstem vasomotor center-mediated CNS activation • Reduces hyperactivity and impulsivity • Helps with regulation of attention

29. Indications • Often used in conjunction with stimulants • Stimulants at max dose or side effects and lack effectiveness • May help modulate mood level • Tics related to stimulant use • Sleep disturbances • Comorbid aggression

30. Side Effects Sedation Mild decreases in HR and BP Abdominal pain Dizziness Dry mouth Constipation Need to discontinue medications slowly because of rebound hypertension and tachycardia

31. Dosing • Intuniv – FDA approved • Extended release – once daily • 1-4 mg daily • Costly • Tenex • BID to TID dosing • Start at 0.5 mg and gradually increase to a max of 4 mg/ day • Clonidine • QID dosing • 0.05mg, 0.1mg and 0.2mg

32. Evaluation Monitor after one to two weeks with med change Evaluate every three months Monitor height and weight at each visit Reevaluate ADHD rating scales Consider school updates, grade reports Reconsider diagnosis with non-responders or co-morbidity Monitor for CV risk factors, tics, other SE, etc.

33. Oppositional Defiant Disorder (ODD) • Prevalence – 2-16 % of school age children • Can be diagnosed as early as 3 years of age, and typically diagnosed by 8 years of age. • Not typically diagnosed in adolescence. • More common in boys than girls prior to adolescence, there after sex ratio is equal • Etiology • Genetic • Temperamental Predisposition • Coercive interactions with parents

34. Diagnosis • DSM – IV –TR (Four behaviors for at least six months) • Loses temper • Argues with adults • Defies or refuses to comply with requests • Deliberately annoys people • Blames others for mistakes or behaviors • Touchy or easily annoyed by others • Angry and resentful • Spiteful or vindictive

35. Treatment • Behavioral Therapy • Preschoolers • Parent-Child Interaction Therapy • Improves self-esteem • Increases parent-child interaction • Reduces coercive parent interactions • School Age Children • Parent Management Training • Use of contingency Management • Reduction of Aversive Punishment • Increase positive reinforcement • Set firm consistent rules • Social skills training (practice appropriate responses)

36. Pharmacological • Currently, no FDA approval for medication treatment of ODD • Few studies have shown effectiveness with the use of medications • Most studies have examined comorbid ADHD and ODD • Methylphenidate • Atomoxetine • Reduction of oppositional behaviors (Turgay, 2009)

37. Atypical Antipsychotics • Treatment of aggression • Risperidone • Effective in children 5 -12 years of age with subaverage intellectual functioning (Turgay et al., 2003)

38. Conduct Disorder • Incidence/Prevalence • 1-10% of population • More common in boys than girls (4:1 to 12:1 ration) • Etiology • More common with parental psychopathology • Harsh, punitive punishment • Substance use • Child abuse and neglect • Divorced families

39. Etiology (cont.) • Urban environments • Lack of social support system • Neurobiological • Possible decreased noradrenergic functioning • Possible elevated serotonin levels

40. Diagnosis • DSM – IV – TR (Three or more in past 12 months) • Aggression to people and animals • Bullies, threatens or intimidates • Initiates physical fights • Use of weapons to cause harm • Physically cruel to animals and humans • Stolen while confronting a victim • Forces sexual activity

41. Destruction of property • Engaged in fire setting or serious damage • Deliberately destroyed property • Deceitfulness or Theft • Breaking into home • Lies to obtain goods or favors or avoid obligations • Stolen items of nontrivial value • Serious violations or rules • Stays out late at night • Runs away from home at least twice • Truant from school

42. Treatment • Multisystemic Therapy • Individual, Group and Family Therapy • Behavioral Therapy • Begin treatment as early as possible • Social Skills Training • Family support interventions • Boot camps • Be aware of Deviant Training • Residential Treatment

43. Pharmacological Treatment • No FDA approval for medications for Conduct Disorders • If behavioral interventions have failed – consider: • Off label use • Methylphenidate • Atypical Antipsychotics - treatment of aggression • risperidone (Risperdal) • aripiprazole (Abilify)

45. References AACAP (2007). Practice parameters for the assessment and treatment of children and adolescents with oppositional defiant disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 1, 126-141. Dittman, R. W. et al. (2011). Atomoxetine versus placebo in children and adolescents with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder: A double-blind, randomized, multicenter trial in Germany. Journal of Child and Adolescent Psychopharmacology, 21, 2, 97-110. Eyberg, S. M., Nelson, M. M., & Boggs, S.R. (2008). Evidenced-based psychosocial treatments for children and adolescents with disruptive behaviors. Journal of Clinical Child & Adolescent Psychology, 37, 215-237. Garland, A. F. et al. (2008). Identifying common elements of evidence-based psychosocial treatment for children’s disruptive behavior problems. Journal of American Academy of Child and Adolescent Psychiatry, 47, 505-514. Garnock-Jones, K. P., & Keating, G. M. (2009). Atomoxetine. A review of its use in attention-deficit hyperactivity disorder in children and adolescents. Pediatric Drugs, 11 ,203-226. Greydanus, D. E., Nazeer, A., & Patel, D. (2009). Psychopharmacology of ADHD in pediatrics; current advances and issues. Neuropsychiatric Disease and Treatment, 5, 171-181. Kaplan, G. & Newcorn, J. H. (2011). Pharmacotherapy for child and adolescent attention-deficit hyperactivity disorder. Pediatric Clinics of North America, 58, 99-120. Kratochvil, C. et al. (2005) Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. Journal of the American Academy of Child and Adolescent Psychiatry, 44, 915-924. Plizka, S. et al. (2007). Practice parameters for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 46, 7, 894-921. Turgau, A. et al. (2002). Long-term safety and efficacy of risperidone for the treatment of disruptive behavior disorders in children with subaverage IQs. Pediatrics, 110, e 34 DOI:10.1542/peds. 110.3 e34 Turgay, A. (2009). Psychopharmacological treatment of oppositional defiant disorder. CNS Drugs, 23, 1, 1-17.