#CHAIR2016. September 15 17, 2016 The Biltmore Hotel Miami, FL. Sponsored by

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1 #CHAIR2016 September 15 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

2 Pediatric Bipolar Disorder: Diagnosis and Management Karen Dineen Wagner, MD, PhD University of Texas Medical Branch Galveston, TX

3 Karen Dineen Wagner, MD, PhD Disclosures (Past 12 Months) Honoraria: UBM Medica LLC; American Society of Clinical Psychopharmacology (ASCP)

4 Off-Label Use Medications discussed in this presentation are off-label for the treatment of bipolar I disorder, manic or mixed episodes in youth, with the exception of lithium, aripiprazole, quetiapine, risperidone, olanzapine and asenapine.

5 Screening for Adolescent Bipolar Disorder

6 Mood Disorder Questionnaire- Adolescent Version (MDQ-A) Screening Criteria 5/13 Symptoms from Question 1 1. Has there ever been a time for a week or more when your adolescent was not his/her usual self and YES NO felt too good or excited? was so irritable that he/she started fights or arguments with people? felt he/she could do anything? needed much less sleep? couldn t slow his/her mind down or thoughts raced through his/her head? was so easily distracted by things? had much more energy than usual? was much more active or did more things than usual? Wagner KD et al. J Clin Psychiatry. 2006;67(5):

7 Mood Disorder Questionnaire- Adolescent Version (continued) had many boyfriends or girlfriends at the same time? Yes on Question 2 was more interested in sex than usual? did many things that were foolish or risky? spent too much money? used more alcohol or drugs? 2. If you checked YES to more than one of the above, have several of these ever happened to your adolescent during the same period of time? Moderate or Serious on Question 3 3. How much of problems did any of these cause your adolescent like school problems, failing grades, problems with family and friends, legal troubles? Please circle one response only. No problem Minor problem Moderate problem Serious problem Wagner KD et al. J Clin Psychiatry. 2006;67(5):

8 Diagnosis of Pediatric Bipolar Disorder

9 Bipolar I Disorder DSM-5 Criteria Manic Episode Elevated, expansive, irritable mood for 1 week (any duration if hospitalized) AND Increased goal-directed activity or energy Three or more symptoms (four if mood is only irritable) Inflated self esteem, grandiosity Decreased need for sleep Talkative, pressured speech Flight of ideas, racing thoughts Distractibility Impairment or hospitalization American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed

10 Course of Pediatric Bipolar Disorder

11 8-Year Follow-up of Children with Bipolar I Disorder Cumulative*Frequency*of* Recovery*from*First*Manic* Episode Baseline: N = 115 children, mean age Follow%Up((years) Geller B, et al. Arch Gen Psychiatry. 2008;65(10): Recovery Rate 88%

12 Eight Year Follow-up of 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):

13 Management of Pediatric Bipolar Disorder

14 Treatment of Early-Age Mania Study (TEAM Study) 279 youths, ages 6 to 15 BD-I, Manic or Mixed Risperidone n = 89 Lithium n = 90 Divalproex n = 100 Geller B, et al. Arch Gen Psychiatry. 2012;69(5):

15 TEAM Study: Clinical Global Improvement at 8 weeks 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Responder3(CGIFIM3=3Much/Very3Much3Improved) 68.5% 35.6% 24.0% Risperidone3(n3=389) Lithium3(n3=390) Divalproex3(n3=3100) Intent to treat: dropout = nonresponder Risperidone vs lithium: p <.001; Risperidone vs. Divalproex: p <.001; Lithium vs. Divalproex: p =.20 Geller B, et al. Arch Gen Psychiatry. 2012;69(5):

16 FDA Approved Medications for Pediatric Bipolar I Disorder, Mixed or Manic Medication Approved Age Range (y) Asenapine Aripiprazole Olanzapine Quetiapine Risperidone Lithium Source: PI for asenapine; PI for aripiprazole; PI for olanzapine; PI for quetiapine; PI for risperidone; PI for lithium. Drugs@FDA Website:

17 Child and Family-Focused Cognitive-Behavioral Therapy for Pediatric Bipolar Disorder 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 CFF-CBT, child and family-focused cognitive-behavioral therapy West AE, et al. J Can Acad Child Adolesc Psychiatry. 2009;18(3):

18 #CHAIR2016 Questions Answers &

19 #CHAIR2016 Supplemental Slides

20 Complete Presentation

21 #CHAIR2016 September 15 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

22 Pediatric Bipolar Disorder: Diagnosis and Management Karen Dineen Wagner, MD, PhD University of Texas Medical Branch Galveston, TX

23 Karen Dineen Wagner, MD, PhD Disclosures (Past 12 Months) Honoraria: UBM Medica LLC; American Society of Clinical Psychopharmacology (ASCP)

24 #CHAIR2016 Learning Objective 1 Review the genetics and lifetime prevalence of pediatric bipolar disorder

25 #CHAIR2016 Learning Objective 2 Discuss the DSM-5 criteria for pediatric bipolar disorder

26 #CHAIR2016 Learning Objective 3 Describe the FDA approved medications for the treatment of pediatric bipolar I disorder, mixed or manic

27 Off-Label Use Medications discussed in this presentation are off-label for the treatment of bipolar I disorder, manic or mixed episodes in youth, with the exception of lithium, aripiprazole, quetiapine, risperidone, olanzapine and asenapine.

28 Lifetime Prevalence of Adolescent Bipolar Disorder National Comorbidity Survey Adolescent Supplement Face-to-face study of 10,123 US adolescents, years Modified Version of World Health Organization Composite International Diagnostic Interview Sex Age Severe Impairment Total Female % Male % % Bipolar I or II Disorder Merikangas KR et al. JAACAP. 2010;49:

29 Risk of Offspring with Bipolar Disorder No Parent n = 2,239,553 Number of Parents with Bipolar Disorder 1 Parent n = 11,995 2 Parents n = 83 Risk of BD in Offspring (Offspring n = 1,080,030) 0.48% (Offspring n = 23,152) 4.4% (Offspring n = 146) 24.9% National register based cohort study in Denmark Gottesman II, et al. Arch Gen Psychiatry. 2010;67(3):

30 Mood Disorder Questionnaire- Adolescent Version (MDQ-A) Screening Criteria 5/13 Symptoms from Question 1 1. Has there ever been a time for a week or more when your adolescent was not his/her usual self and YES NO felt too good or excited? was so irritable that he/she started fights or arguments with people? felt he/she could do anything? needed much less sleep? couldn t slow his/her mind down or thoughts raced through his/her head? was so easily distracted by things? had much more energy than usual? was much more active or did more things than usual? Wagner KD et al. J Clin Psychiatry. 2006;67(5):

31 Mood Disorder Questionnaire- Adolescent Version (continued) had many boyfriends or girlfriends at the same time? Yes on Question 2 was more interested in sex than usual? did many things that were foolish or risky? spent too much money? used more alcohol or drugs? 2. If you checked YES to more than one of the above, have several of these ever happened to your adolescent during the same period of time? Moderate or Serious on Question 3 3. How much of problems did any of these cause your adolescent like school problems, failing grades, problems with family and friends, legal troubles? Please circle one response only. No problem Minor problem Moderate problem Serious problem Wagner KD et al. J Clin Psychiatry. 2006;67(5):

32 Bipolar I Disorder DSM-5 Criteria Manic Episode Elevated, expansive, irritable mood for 1 week (any duration if hospitalized) AND Increased goal-directed activity or energy Three or more symptoms (four if mood is only irritable) Inflated self esteem, grandiosity Decreased need for sleep Talkative, pressured speech Flight of ideas, racing thoughts Distractibility Impairment or hospitalization American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed

33 Comorbid Disorders Associated with Bipolar Disorder in Children and Adolescents Estimated Prevalence, % ADHD Substance abuse 2, Anxiety disorder 3-9, Obsessive compulsive disorder 4 Panic 5 Generalized anxiety disorder 6 Social anxiety 7 PTSD 8 2 anxiety disorders 9 Oppositional defiant disorder 10,11 75 Conduct disorder 10, Soutullo CA, et al. J Affect Disord. 2002;70(3): ; 2. West SA, et al. Biol Psychiatry. 1996;39(6): ; 3. Geller B, et al. J Child Adolesc Psychopharmacol. 2000;10(3): ; 4. Wilens TE, et al. J Am Acad Child Adolesc Psychiatry. 1999;38(6): ; 5. Masi G, et al. Can J Psychiatry. 2001;46(9): ; 6. Birmaher B, et al. J Clin Psychiatry. 2002;63(5): ; 7. Jerrell JM, et al. Bipolar Disord. 2004;6(4): ; 8. Carlson GA, et al. J Affect Disord. 1998;51(2): ; 9. Kovacs M, et al. J Am Acad Child Adolesc Psychiatry. 1995;34(6): ; 10. Masi G, et al. Biol Psychiatry. 2006;59(7): ; 11. Sala R, et al. J Clin Psychiatry. 2010; 71: ; 12. Goldstein BI, et al. J Am Acad Child Adolesc Psychiatry. 2013;52:

34 Pediatric Bipolar Disorder and Suicidality Weighted Mean Prevalence Suicidal Ideation % Suicide Attempts % Past Current Review of 14 Studies (n = 1595) reporting suicidality and pediatric bipolar disorder Hauser M, et al. Bipolar Disorders. 2013;15(5):

35 8-Year Follow-up of Children with Bipolar I Disorder Cumulative*Frequency*of* Recovery*from*First*Manic* Episode Baseline: N = 115 children, mean age Follow%Up((years) Geller B, et al. Arch Gen Psychiatry. 2008;65(10): Recovery Rate 88%

36 Eight Year Follow-up of 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):

37 FDA Approved Medications for Pediatric Bipolar I Disorder, Mixed or Manic Medication Approved Age Range (y) Asenapine Aripiprazole Olanzapine Quetiapine Risperidone Lithium Source: PI for asenapine; PI for aripiprazole; PI for olanzapine; PI for quetiapine; PI for risperidone; PI for lithium. Drugs@FDA Website:

38 FDA Approved Medications for Pediatric Bipolar I Depression Medication Approved Age Range (y) Olanzapine / Fluoxetine Medications FDA approved for bipolar I depression in adults: Olanzapine/fluoxetine Quetiapine Lurasidone (currently in clinical trial for pediatric bipolar I depression (10-17) Source: PI for olanzapine/fluoxetine Drugs@FDA Website:

39 Example of Controlled Trial of Atypical Antipsychotic for Pediatric Bipolar I Disorder Mean Change in YMRS Score 0!2!4!6!8!10!12!14!16!18 * ** ** RIS+0.5! 2.5mg/day RIS+3!6mg/day Placebo!20 0 Baseline Week 169 youths, ages 10 to 17 years old, with Bipolar I Disorder, manic or mixed episodes; *p <.01; **p <.001; ***p =.002 Haas M, et al. Bipolar Disorders. 2009;11(7): Percentage Response Rate ** ***

40 Response Rates for Second Generation Antipsychotics ( 50% reduction in YMRS) 45 65% YMRS, Young Mania Rating Scale Tohen, et al. Am J Psychiatry. 2007;164(10): ; DelBello, et al. Presented at AACAP 2007 Annual Meeting, Boston MA; Findling RL, et al. J Clin Psychiatry. 2009;70(10): ; Hass M, et al. Bipolar Disorders. 2009;11(5):

41 Lithium for Bipolar I Disorder, Mixed or Manic in Youth (7-17 years) Change in YMRS Lithium (Mean Level 0.98mEq/L) (n = 51) Placebo (n = 28) * * -30 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Adverse events: Significant increase in thyrotropin concentration; (3.0 miu/l); *p <.05 Findling RL, et al. Pediatrics. 2015;136(5):

42 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 ER (80 µg/l) 4 Oxcarbazepine Topiramate *No statistically significant difference between medication and placebo on change in Young Mania Rating Scale from baseline to endpoint ER, extended release 1. Wagner KD, et al. J Am Acad Child Adolesc Psychiatry. 2009;48(5): ; 2. Wagner, et al. Am J Psychiatry. 2006;163(7): ; 3. DelBello MP, et al. J Am Acad Child Adolesc Psychiatry. 2005;44(6):

43 Treatment of Early-Age Mania Study (TEAM Study) 279 youths, ages 6 to 15 BD-I, Manic or Mixed Risperidone n = 89 Lithium n = 90 Divalproex n = 100 Geller B, et al. Arch Gen Psychiatry. 2012;69(5):

44 TEAM Study: Dose/Blood Levels Week 1 Week 2 Week 3 Week 4 Week 6 Week 8 Lithium level Mean ± SD; meq/l Valproate level Mean ± SD; μg/ml 0.5 ± ± ± ± ± ± ± ± ± ± ± ± 27 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. Arch Gen Psychiatry. 2012;69(5):

45 TEAM Study: Clinical Global Improvement at 8 weeks 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Responder3(CGIFIM3=3Much/Very3Much3Improved) 68.5% 35.6% 24.0% Risperidone3(n3=389) Lithium3(n3=390) Divalproex3(n3=3100) Intent to treat: dropout = nonresponder Risperidone vs lithium: p <.001; Risperidone vs. Divalproex: p <.001; Lithium vs. Divalproex: p =.20 Geller B, et al. Arch Gen Psychiatry. 2012;69(5):

46 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, RA et al. J Am Acad Child Adolesc Psychiatry. 2005;44(3):

47 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 RA, et al. J Am Acad Child Adolesc Psychiatry. 2005;44(3):

48 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):

49 Cardiometabolic Risk of Atypical Antipsychotics Medication Total Cholesterol Triglycerides Highlighted numbers in yellow are significant at p <.05 Correll CU, et al. JAMA. 2009;302(16): Metabolic Non-HDL Ratio of Triglycerides to HDL Olanzapine Quetiapine Risperidone Aripiprazole

50 Antipsychotics and Type 2 Diabetes in Youth Retrospective cohort study of 25,858 youth in Tennessee Medicaid who initiated antipsychotics compared to control group who initiated another psychotropic Probability of Type 2 Diabetes Years of Follow-Up Bobo WV, et al. JAMA Psychiatry. 2013;70(10): Type 2 Diabetes per 10,000 Person-Years Control <5 g 5-99 g 100 g Cumulative Antipsychotic Dose, Chlorpromazine Equivalents

51 Risperidone Discontinuation and Cardiometabolic Outcomes 101 patients ages 7 to 17 treated with risperidone for 36 months Follow-up 1.5 years Outcome Discontinuation of antipsychotic reversed weight gain and improved cardiometabolic parameters Calarge CA, et al. J Child Adolesc Psychopharmacol. 2014; 24(3):

52 Strategies for Prevention and Management of Weight Gain Healthy lifestyle behaviors 12-item list related to eating habits and exercise Correll CU, et al. J Am Acad Child Adolesc Psychiatry. 2006;45(7):

53 Controlled Trial of Flax Oil in Pediatric Bipolar Disorder 51 youths (ages 6 to 17 years) with BD-I or BD-II Randomized to flax oil capsules (omega-3 fatty acids α-linolenic acid) or olive oil placebo adjunctively or as monotherapy Doses titrated to 12 capsules per 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 YMRS, Young Mania Rating Scale; CDRS-R, Child Depression Rating Scale-Revised Gracious BL, et al. Bipolar Disord. 2010;12(2):

54 Multinutrient Supplement for Pediatric Bipolar Spectrum Disorders 10 children (6-12 yrs) received a 36 ingredient multinutrient supplement, EM-Powerplus (EMP+) for bipolar spectrum disorder. Contains minerals, vitamins, amino acids and antioxidants Dosage 1 capsule t.i.d. to 5 capsules t.i.d. Outcome 70% completed study Four serum vitamin concentrations increased; Vitamin A-retinol, vitamin B6, Vitamin E-α tocopherol, folate Over 8 weeks 37% decrease in depression scores 45% decrease in mania scores Adverse events: insomnia, gastrointestinal upset Frazier EA, et al. J Alternative and Complementary Medicine. 2012;18(7): ; Frazier EA, et al. J Child and Adolsc Psychopharm. 2013;23(8):

55 Intranasal Ketamine for Pediatric Bipolar Disorder Retrospective chart review of 12 youth ages 6 to 19 years with treatment refractory bipolar I disorder Received intranasal ketamine* doses mg, administered at intervals of 3-7 days Therapeutic benefit within 1-24 hours; lasted hours Improvement in mania, anxiety, aggression Most common adverse events Dizziness, elated mood, spaced out *Not FDA approved for bipolar disorder Papolos DF, et al. J Affect Dis. 2013;147:

56 Child and Family-Focused Cognitive-Behavioral Therapy for Pediatric Bipolar Disorder 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 CFF-CBT, child and family-focused cognitive-behavioral therapy West AE, et al. J Can Acad Child Adolesc Psychiatry. 2009;18(3):

57 #CHAIR2016 Questions Answers &