Maximizing Treatment Success New Strategies for Treating ADHD and Associated Comorbidities

1. Maximizing Treatment SuccessNew Strategies for Treating ADHD and Associated Comorbidities Provided by the Network for Continuing Medical Education This CME activity is supported by an educational grant from Shire US Inc.

2. Disclosure Statement The Network for Continuing Medical Education requires that CME faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity.

3. Faculty Disclosure

4. Treatment of ADHD in Children

5. Learning Objectives • Characterize the comorbid disorders commonly associated with attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults • Apply effective approaches to screening for associated comorbidities, such as mood disorders, substance use disorder, and disruptive behavior disorders, in patients with ADHD • Discuss how to differentiate between ADHD and a disorder with similar features, and ADHD comorbid with that disorder • Assess current pharmacologic and behavioral treatment strategies for patients with ADHD and various comorbid disorders • Outline a comprehensive treatment plan that includes other healthcare professionals in the management of patients with ADHD and associated comorbidities

6. Steven R. Pliszka, MD, Chair Professor and Chief Division of Child and Adolescent Psychiatry University of Texas Health Science Center at San Antonio San Antonio, Texas Russell A. Barkley, PhD Research Professor Department of Psychiatry SUNY Upstate Medical University Syracuse, New York Adjunct Professor of PsychiatryMedical University of South Carolina Charleston, South Carolina James Robert Batterson, MD Child Psychiatrist Children’s Mercy Hospitals and Clinics Kansas City, Missouri William W. Dodson, MD Private PracticeSpecializing in Adult ADHD Denver, Colorado Robert D. Hunt, MD CEO and Medical Director Center for Attention and Hyperactivity Disorders Nashville, Tennessee Contributing Faculty

7. ADHD in Children: Objective • Present strategies for diagnosis and treatment of disorders commonly comorbid with ADHD in children and adolescents • Disruptive behavior disorders • Anxiety • Depression • Bipolar disorder

8. Empirically Proven Treatments for ADHD in Children: Psychopharmacology • Stimulants • Methylphenidate (Ritalin®, Concerta®) • Mixed amphetamine salts (Adderall®/Adderall XR®) • Nonstimulant • Atomoxetine (Strattera®) • Other noradrenergic medications • Bupropion (Wellbutrin®) • Tricyclic antidepressants • Desipramine (Norpramin®) • Antihypertensives • Clonidine (Catapres®) • Guanfacine (Tenex®) Physicians’ Desk Reference. 59th ed. Montvale, NJ: Thomson PDR; 2005.

9. Empirically Proven Treatments for ADHD in Children: Psychosocial Interventions • Parent education about ADHD1,2 • Parent training in child management3 • Children (<11 yrs, 65%-75% respond) • Adolescents (25%-30% show reliable change) • Family therapy for teens: problem-solving, communication training4 • 30% show change • Best to combine with BMT to reduce dropouts • Weiss M. Child Adolesc Psychiatr Clin North Am. 1992;1:467-479. • Dulcan M. J Am Acad Child Adolesc Psychiatry. 1997;36:85S-121S. • Barkley RA. Defiant Children: A Clinician’s Manual for Assessment and Parent Training. 2nd ed. New York: Guilford Press; 1997. • Murphy K. J Clin Psychol. 2005;61:607-619.

10. Empirically Proven Treatments for ADHD in Children: Psychosocial Interventions (cont.) • Teacher education about ADHD • Teacher training in classroom behavior management • Special education services (IDEA, section 504) • Regular physical exercise • Residential treatment (5%-8%) • Parent/family services (25+) • Parent/client support groups (CHADD, ADDA, independents) Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. 2nd ed. New York: Guilford Press; 1998.

11. Major Behavioral Tactics for ADHD Balance the following two strategies: • Altering antecedents – getting proactive: • Giving effective instructions • Altering performance settings • Point-of-performance prompts and cues • Altering consequences – being reactive: • Positive reinforcement (tokens, rewards, etc.) • Punishment (time outs, grounding, fines, etc.) • Changing schedules (increasing frequency and immediacy of consequences) DuPaul GJ, Stoner G. ADHD in the Schools. 2nd ed. New York: Guilford Press; 2003.

12. ADHD in Childhood: Common Comorbid Diagnoses Approximate Prevalence Rate in Children With ADHD (%) 0 10 20 30 40 50 60 Oppositional defiant disorder Conduct disorder Mood disorders Anxiety disorders Male Female Learning disorders Pliszka SR. J Clin Psychiatry. 1998;59(suppl 7):50-58. Biederman et al. J Am Acad Child Adolesc Psychiatry. 1999;38:966-975. Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351. Spencer et al. Pediatr Clin North Am. 1999;46:915-927.

13. Disruptive Behavior Disorders

14. Conduct Disorder (CD) • A repetitive and persistent pattern of behavior in which the basic rights or well-being of others is disregarded1 • Common symptoms1: • Aggression to people or animals • Destruction of property • Deceitfulness or theft • Serious violation of rules • CD may be more severe and persistent when comorbid with ADHD2 • American Psychiatric Association. DSM-IV; 1994:85-91. • Kuhne et al. J Am Acad Child Adolesc Psychiatry. 1997;36:1715-1725.

15. Oppositional Defiant Disorder (ODD) • A negativistic, hostile, and defiant pattern of behavior that varies greatly in severity • Common symptoms • Often loses temper • Often actively defies adults • Often deliberately annoys people American Psychiatric Association. DSM-IV; 1994:91-94.

16. Nature of CD and ODD • A descriptive diagnosis; does not imply etiology • ODD may be secondary to ADHD • CD/ODD may occur even without ADHD • CD/ODD are sometimes due to environmental factors (late onset) • CD with ADHD may represent a distinct familial subtype and genetic variant of ADHD • CD with ADHD is a worse condition than either alone or than their combination would suggest • Most likely has multiple causes

17. ADHD Without and With CD/ODD Note: Symbol shows rate relative to controls.

18. Psychopharmacology of CD/ODD • ADHD children with (and without) CD/ODD respond to stimulants1 • Indeed, effect-size changes in ODD symptoms may be as large as those in ADHD symptoms in comorbid cases • No evidence that stimulants increase aggression at appropriate doses; evidence shows decreased aggression2 • Relative to placebo, ADHD children on stimulants engage in less antisocial behavior • MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1073-1086. • Spencer et al. J Am Acad Child Adolesc Psychiatry. 1996;35:409-432.

19. ADHD and CD/ODD: Psychopharmacologic Recommendations • Divalproex: may be effective for explosive temper and mood lability1 • Risperidone: has reduced disruptive behavior and hyperactivity2 • Atomoxetine: has produced meaningful improvement in ADHD and ODD symptoms3 • Donovan et al. Am J Psychiatry. 2000;157:818-820. • Aman et al. J Child Adolesc Psychopharmacol. 2004;14:243-254. • Newcorn et al. J Am Acad Child Adolesc Psychiatry. 2005;44:240-248.

20. Psychosocial Treatment of ADHD and CD/ODD in Children • When CD/ODD is present, interventions focused on parenting are essential given the recognized contribution of parenting to both disorders • Parent training (PT) in behavior management methods has strong empirical support, particularly for addressing the ODD problems in ADHD children • PT is most effective (65%-75%) with elementary school-age children but declines markedly by adolescence (30%) • Problem-solving communication training combined with behavior management training has the greatest evidence for effectiveness (30%) for those 14 and older • Traditional family therapies are less helpful (10% response rate) Barkley RA. Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. 2nd ed. New York: Guilford Press; 1998.

21. Psychosocial Treatment of ADHD and CD/ODD in Children (cont.) • Where CD is present, parental psychological disorders are highly likely and may require additional intervention beyond those for the ADHD child1 • Family relocation to better neighborhoods and schools may also be important and assist with disrupting deviant peer groups, criminogenic neighborhood environments, and ineffective schools2 • Avoid group treatment programs that bring antisocial youth together, as they have been shown to increase antisocial behavior outside the group (deviancy training)2 • Multisystemic therapy that involves therapists in the home setting daily is an empirically supported alternative to traditional clinic-based therapies or incarceration for juveniles3 • Biederman et al. J Am Acad Child Adolesc Psychiatry. 1996;35:343-351. • Dishion et al. Am Psychol. 1999;54(9):755-764. • Henggelar et al. J Am Acad Child Adolesc Psychiatry. 2003;42:543-551.

22. Anxiety and Depressive Disorders

23. ADHD and Anxiety Disorders • Children with ADHD and comorbid anxiety disorders tend to display: • High levels of arousal • Fearfulness, separation anxiety • Phobias, fear of sleeping alone • Fear of social situations • Anxiety beyond that associated with consequences of misbehavior • Anxiety symptoms must be overt; should not be assumed to be present based on ADHD symptoms alone ONLY SIGNIFICANT, IMPAIRING ANXIETY SHOULD BE A FOCUS OF PHARMACOLOGIC TREATMENT Spencer et al. Pediatr Clin North Am. 1999;46:915-927.

24. Major depressive disorder Pervasive sadness or irritability nearly every day Loss of energy Guilt Serious suicidal ideation Suicidal gestures Cannot be reassured Chronic low self-esteem Dysphoria or “demoralization” Brief periods of sadness when frustrated Energy normal Lack of guilt except when in trouble Brief threats of self-harm when frustrated Responds to redirection Positive attitude about good areas of function ADHD and Comorbid Depression ONLY MAJOR DEPRESSIVE DISORDER SHOULD BE A FOCUS OF ANTIDEPRESSANT TREATMENT American Psychiatric Association. DSM-IV; 1994:317-327, 339-350.

25. Pharmacologic Treatment of Depression in Children FDA Meta-analysis • Pooled all studies, published and unpublished • Blinded reviewers at Columbia assessed each adverse event as to its self-harm potential • N >4,000 • No completed suicides • 4% suicidal ideation on drug vs 2% on placebo, statistically significant difference FDA Public Health Advisory. October 15, 2004. Available at: http://www.fda.gov/cder/drug/antidepressants/SSRIPHA200410.htm. Accessed June 6, 2005.

26. Treatment for Adolescents With Depression Study (TADS) • Response rates • Fluoxetine + CBT: 71% • Fluoxetine alone: 61% • CBT alone: 43% • Placebo: 35% • Presence of SI • 29% at baseline • All 4 groups improved significantly, but SI still higher in SSRI group CBT = cognitive-behavioral therapy; SI = suicidal ideation; SSRI = selective serotonin reuptake inhibitor. March et al. JAMA. 2004;292:807-820.

27. Treatment of ADHD With MDD:Stimulant First vs Antidepressant First • Stimulant first1,2 • ADHD chief complaint • ADHD symptoms more disabling • MDD found on interview, no current functional impairment from depression • Mild neurovegetative signs • ADHD symptoms clearly preceded MDD symptoms • Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management. New York: Guilford Press; 1999. • Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.

28. Treatment of ADHD With MDD: Stimulant First vs Antidepressant First (cont.) • Antidepressant first1,2 • Clear history of stimulant nonresponse • Prominent neurovegetative signs/health compromised • MDD present complaint • ADHD symptoms late onset or coincident with MDD symptoms • Suicidal/psychotic • Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management. New York: Guilford Press; 1999. • Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.

29. Treatment of ADHD With Anxiety • Start with stimulant first unless1,2: • Full-blown panic symptoms • Full-blown separation anxiety with complete refusal to separate, but: • Studies conflict on whether children with anxiety have poorer response to stimulants • Consider using atomoxetine for both ADHD and anxiety or as a supplement to stimulant treatment • May add SSRI to stimulant to treat anxiety1,2 • Pliszka et al. ADHD with Comorbid Disorders: Clinical Assessment and Management. New York: Guilford Press; 1999. • Pliszka et al. J Am Acad Child Adolesc Psychiatry. 2000;39:908-919.

30. Psychosocial Treatment of ADHD With Anxiety/Depression • Comorbid ADHD/anxiety shows best response to behavioral and social skills intervention1 • Cognitive therapy relative to ADHD alone or with other disruptive disorders may be helpful2 • In behavioral token systems, keep thresholds for success low initially; high likelihood of success eliminates worry about earning quotas for privileges • Low self-esteem is specifically associated with comorbid depression, not due to ADHD • Use “go slow” approach to punishment contingencies (eg, time outs) in comorbid ADHD/depression so as not to contribute to depressive cognitive schemas • Start with all-reward programs until depression symptoms lift, then introduce selective mild punishments • MTA Cooperative Group. Arch Gen Psychiatry. 1999;56:1088-1096. • Brent et al. Arch Gen Psychiatry. 1997;54:877-885.

31. Bipolar Disorder

32. DSM-IV Bipolar Disorders • Bipolar I disorder (manic-depressive illness) • Manic • Depressed • Mixed • Bipolar II disorder • Hypomania + depression • Cyclothymia • Hypomania • Depression • Bipolar disorder NOS American Psychiatric Association. DSM-IV; 1994:350-366.

33. Bipolar Disorders in a Community Sample of Older Adolescents • 1,709 high school students • Mean age, 16.6 ± 1.2 yr • Randomly selected from 9 senior high schools • Time 1 assessment (1987-1989) • Adolescent Interview • K-SADS/E/P • Time 2 assessment (14 mos later) • K-Life Lewinsohn et al. J Am Acad Child Adolesc Psychiatry. 1995;34:454-463.

34. Bipolar Disorders in a Community Sample of Older Adolescents:Summary • 18 Cases – prevalence of ~1% • 2 Bipolar I disorder • 11 Bipolar II disorder • 5 Cyclothymia • 97 Bipolar disorder NOS • Significant functional impairments • High rates of: • Psychiatric comorbidity • Mental health service utilization Lewinsohn et al. J Am Acad Child Adolesc Psychiatry. 1995;34:454-463.

35. Bipolar Disorder:Adult vs Child Criteria • Elation vs irritability1 • Definition of an “episode”2 • “Distinct period” • Simple cycling • Complex cycling • Strict adult criteria vs developmentally appropriate criteria • Geller et al. J Affect Disord. 1998;51:81-91. • Wozniak et al. J Clin Psychiatry. 2001;62:10-15.

36. Bipolar Disorder in Children and Adults:Different Developmental Trajectories? Pediatric Euphoric BPs ? Adult Subtype Manic BP NOS? Mood State Euthymic ADHD Rx Adolescent Subtype BP II or I Depressed 0 2 4 6 8 10 12 14 16 18 20 22 Age/Years

37. Treatment of Pediatric Bipolar Disorder:Mood Stabilizers • Study of 42 outpatients (mean age, 11.4 yr) with bipolar I or II disorder randomized to open treatment with lithium, divalproex, or carbamazepine over a 6- to 8-week period • Low-dose chlorpromazine allowed as “rescue medication” • All 3 mood stabilizers showed a large effect size, as measured by a ≥50% change from baseline to exit in the Y-MRS scores Y-MRS = Young Mania Rating Scale. Kowatch et al. J Am Acad Child Adolesc Psychiatry. 2000;39:713-720.

38. Mood Stabilizer Treatment of Pediatric Bipolar Disorder: Responders’ Pattern of Response 35 30 25 20 15 10 5 0 Carbamazepine Valproate Lithium Mean Young MRS Score Random. 1 2 3 4 5 6 7 8 Week Reproduced with permission from Kowatch et al. J Am Acad Child Adolesc Psychiatry. 2000;39:713-720.

39. Potential Mood Stabilizers • Gabapentin (Neurontin®): negative • Lamotrigine (Lamictil®): BP depressed, maintenance of BP, risk of rash/Stevens-Johnson syndrome • Tiagabine (Gabitril®): negative • Topiramate (Topamax®): trials in adults negative; trials in children discontinued • Oxcarbazepine (Trileptal®): new risk of rash/Stevens- Johnson syndrome • FDA performing review of anticonvulsants and the risk of suicide

40. Atypical Antipsychotics • Current agents • Risperidone • Olanzapine • Quetiapine • Ziprasidone • Aripiprazole • Powerful • Sometimes necessary • Limit use because of • Sedation • Weight gain Kowatch et al. J Am Acad Child Adolesc Psychiatry. 2005;44:213-235.

41. Placebo Ziprasidone Haloperidol Risperidone Chlorpromazine Olanzapine Clozapine Antipsychotic Weight Gain: Meta-analysis 5 4 3 Kg 2 1 0 - 1 Weight gain Allison et al. Am J Psychiatry. 1999;156:1686-1696.

42. ADHD and Mania: Treatment • If floridly manic, stabilize mood before treating ADHD (or discontinue ADHD treatment until mood stabilized) • Stimulant may be added to mood stabilizer or atypical antipsychotic later • If mania/BP diagnosis is equivocal, treat ADHD first • If all symptoms resolve, mania unlikely • If stimulant or ADHD medication induces partial remission of ADHD and manic symptoms without worsening of manic symptoms, may add atypical antipsychotic or classic mood stabilizer (lithium or valproate) Spencer et al. Attention-deficit/hyperactivity disorder with mood disorders. In: Brown TE, ed. Attention-Deficit Disorders and Comorbidities in Children, Adolescents, and Adults. Washington, DC: American Psychiatric Press; 2000:79-124.

43. ADHD and Mania: Treatment (cont.) • Use diagnosis of intermittent explosive disorder for children with severe aggression but no other symptoms of mania • Atypical antipsychotic, lithium, or valproate may be added to stimulant for treatment of aggression • Do not use atypical antipsychotic for ODD symptoms alone Spencer et al. Attention-deficit/hyperactivity disorder with mood disorders. In: Brown TE, ed. Attention-Deficit Disorders and Comorbidities in Children, Adolescents, and Adults. Washington, DC: American Psychiatric Press; 2000:79-124.

44. Psychosocial Treatment of ADHD and Bipolar Disorder • Limit behavioral contingencies to all positive approaches to reduce explosive outbursts in response to parental limit-setting • Consider Ross Greene’s program for the explosive child • Interventions are more likely to be focused on parental coping with explosive episodes rather than remediation of disruptive behavior • Counsel parents on stress management • ADHD/BPD cases have the highest rates of physical abuse and PTSD of all ADHD cases • Special educational services in BPD/ED classes under IDEA are likely given severely disruptive behavior

45. ADHD in Children: Summary • Strategies for managing ADHD in children comprise a combination of pharmacologic and psychosocial interventions, including parent training in behavior management • These strategies can also be effective in managing disorders commonly comorbid with ADHD • Disruptive behavior disorders • Depression and anxiety disorders • Bipolar disorder • Developing a treatment plan for children with ADHD and comorbid disorders requires careful evaluation of the symptoms and severity of each disorder • Guidelines for effective management of pediatric ADHD and associated comorbidities are evolving, based on research findings and clinical experience