#CHAIR2016. September 16 17, 2016 The Biltmore Hotel Miami, FL. Sponsored by

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1 #CHAIR2016 September 16 17, 2016 The Biltmore Hotel Miami, FL Sponsored by

2 Depression in Children and Adolescents 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 #CHAIR2016 Learning Objective 1 Screen adolescents ages 12 to 18 years for major depressive disorder

5 #CHAIR2016 Learning Objective 2 Describe the common comorbid disorders associated with major depression in children and adolescents

6 #CHAIR2016 Learning Objective 3 Consider best-practice options for the treatment of major depression in adolescents

7 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

8 Lifetime Prevalence of Adolescent Depression National Comorbidity Survey Adolescent Supplement Face-to-face study of 10,123 US adolescents, ages 13 to 18 years Modified version of World Health Organization Composite International Diagnostic Interview Female % Sex Male % Age Severe Impairment Total % MDD or Dysthymia Merikangas KR et al. J Am Acad Child Adolesc Psychiatry. 2010;;49:

9 Screening for Depression in Children and Adolescents Recommendation from US Preventative Task Force Screen for major depressive disorder in adolescents12 to 18 years (PHQ-A highest positive predictive value) Have adequate systems to ensure accurate diagnosis, effective treatment, and appropriate follow-up Current evidence insufficient to assess balance of benefits and harms of screening for major depressive disorder in children 11 years US Preventative Task Force. Annals of Internal Medicine. 2016;;164(5):

10 Patient Health Questionnaire-Adolescent (PHQ-A) Johnson JG, et al. J Adolescent Health. 2002;; 30(3):

11 Major Depression in Youth and Cardiovascular Disease American Heart Association Scientific Statement Major Depression in Youth is moderate risk condition for Accelerated atherosclerosis Early cardiovascular disease (CVD) Goldstein BI, et al. Circulation. 2015;;132(10):

12 Top Ten Causes of DALYs Lost Among Adolescents Unipolar Depressive Disorders Road Injury Iron-deficiency anemia HIV/AIDS Self-harm Back and neck pain Diarrhoeal diseases Anxiety Disorders Asthma Lower respiratory Infections DALYs (in millions) DALYs = Disability-adjusted live years lost World Health Organization 2014, Health for The World s Adolescents,

13 Diagnosis of Major Depression in Children and Adolescents DSM-5 criteria Depressed or irritable mood Diminished interest in activities Appetite or weight changes Sleep disturbance Psychomotor agitation or retardation American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed

14 Diagnosis of Major Depression in Children and Adolescents DSM-5 criteria Fatigue or loss of energy Worthlessness or guilt Diminished concentration or indecisiveness Suicidal ideation, attempt, or plan American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. 5th ed

15 Comorbid Disorders Associated with Major Depression in Children and Adolescents Anxiety disorders Attention-deficit hyperactivity disorder Conduct disorder Substance abuse Anorexia nervosa, bulimia Birmaher, et al. J Am Acad Child & Adolesc Psychiatry. 1996;;35(11):

16 Major Depression and Suicidality in Adolescents Past 12 Months* (%) Suicidal Thought 27.3 Suicidal Plan 9.6 Suicide Attempt 10.8 *Source: National Comorbidity Survey Adolescent Supplement (n = 10,123) Avenevoli S, et al. J Am Acad Child Adolesc Psychiatry. 2015;;54(1):37-44.

17 Outcome of Adolescent Depression 140 adolescents with depressive disorders Psychosocial and/or antidepressant treatment Outcome 3-9 years (mean 6yrs) 93% full remission from index episode 53% recurrence of depressive disorder 79% developed non-mood disorder anxiety, substance use, eating disorders Only 15% had no subsequent depressive episode or other nonmood disorder Melvin GA, et al. J Affective Disorders. 2013;;151(1):

18 FDA Approval for Acute Treatment of Major Depressive Disorder Medication Ages Fluoxetine (3 studies) 1,2, Escitalopram (1 study) Emslie GJ, et al. Arch Gen Psychiatry. 1997;;54(11): Emslie GJ, et al. J Am Acad Child Adolesc Psychiatry. 2002;;41(10): Treatment for Adolescents with Depression Study (TADS) Team. JAMA. 2004;;292(7): Emslie GJ, et al. J Am Acad Child Adolesc Psychiatry. 2009;; 48(7):

19 Other Controlled Pediatric Depression Trials Positive* studies Negative* studies Medication Ages Number of Studies Citalopram Sertraline (a priori pooled analysis)** Citalopram Escitalopram Paroxetine Mirtazapine Nefazadone Venlafaxine * On primary outcome measure, ** Individual trials negative, Not FDA approved for MDD in children and adolescents March J, et al. J Am Acad Child Adolesc Psychiatry. 2004;;43(8): ;; Wagner KD, et al. JAMA. 2003;;290(8): ;;Wagner KD, et al. Am J Psychiatry. 2004;;161(6): ;; Berard R, et al. J Child Adolesc Psychopharmacol. 2006;;16(1-2):59-75;; Keller, et al. J Am Acad Child Adolesc Psychiatry. 2001;;40(7): ;; Emslie G, et al. J Am Acad Child Adolesc Psychiatry. 2006;;45(12): ;; Emilie G, et al. J Am Acad Child Adolesc Psychiatry. 2007;;46(4): ;; Wagner KD, et al. J Am Acad Child Adolesc Psychiatry. 2006;;45(3): ;; Rynn, et al, 2002;; Von Knorring AL, et al. J Clin Psychopharmacol. 2006;;26(3): ;; Rynn M. Presented at 156th Annual Meeting of the American Psychiatric Association;; 2003.

20 Meta-analysis of Antidepressant Trials in Youth with MDD Response Rates Antidepressants 61% Placebo 50% MDD = major depressive disorder, 13 trials, 2910 participants in MDD meta-analysis Bridge JA, et al. JAMA. 2007;;297(15):

21 Maintenance Treatment for Adolescent Depression Acute Phase Sertraline Responders Continuation Phase Sertraline (n = 93) (n = 51) Responders Maintenance Phase Sertraline (n = 13) Placebo (n = 9) 12 weeks 24 weeks 52 weeks Maintained response (no recurrence) at 52 weeks, % Sertraline* 38 Placebo 0 * Not FDA approved for MDD in children and adolescents Cheung A, et al. J Child Adolesc Psychopharmacol. 2008;;18(4):

22 Treatment of Adolescent Depression Study (TADS) 439 adolescent outpatients with major depression Randomized to 12 weeks of: Fluoxetine (10 mg/day to 40 mg/day) CBT with fluoxetine (10 mg/day to 40 mg/day) CBT alone Placebo CBT = cognitive behavioral therapy Treatment for Adolescents with Depression Study (TADS) Study Team. JAMA. 2004;;292:

23 TADS Response Rates CGI 2 Week FLX + CBT FLX CBT PLB 12 73% 62% 48% 35% 18 85% 69% 65% 36 86% 81% 81% FLX = fluoxetine;; PLB = placebo, CGI = clinical global impressions improvement score Treatment for Adolescents with Depression Study (TADS) Study Team. Arch Gen Psychiatry. 2007;;64(10):

24 Treatment of SSRI-Resistant Depression in Adolescents (TORDIA Trial) 334 adolescents with major depression who failed to respond to 8 weeks of SSRI therapy Randomized to 12 weeks of: Different SSRI Different SSRI + CBT Switch to venlafaxine* Switch to venlafaxine* + CBT *Not FDA approved for MDD in children and adolescents;; SSRI = selective serotonin reuptake inhibitor Brent D, et al. JAMA. 2008;;299(8):

25 TORDIA:Clinical Response by Treatment Group (CGI 2 and decrease CDRS-R 50%) % Responders MED CBT SSRI Venlafaxine* No CBT CBT *Not FDA approved for MDD in children and adolescents;; = p =.009;; MED = medical intervention CDRS-R = Children s Depression Rating Scale-revised Brent D, et al. JAMA. 2008;;299(8):

26 TORDIA: Adverse Events SSRI N = 168 SSRI Venlafaxine N = 166 Skin c 2% 8% Venlafaxine* Baseline Week 12 Baseline Week 12 Diastolic blood pressure, mm Hg a Heart rate, bpm b *Not FDA approved for MDD in children and adolescents;; a Venlafaxine vs. SSRI: t = 2.88;; p =.004;; b Venlafaxine vs. SSRI: t = 3.41;; p =.001;; c By medication: χ² = 6.69, p =.01;; Bpm, beats per minute Brent DA, et al. JAMA. 2008;;299(8):

27 Co-Rumination and Co-Problem Solving in Depressed Adolescents Proportion of Problem Talk MDD (n = 29) Control (n = 31) ** * Peer Parent Social Partner for Co-Rumination MDD Control * Peer Parent Social Partner for Co-Problem Solving *p <.05;; **p <.01 Waller JM, et al. J Am Acad Child Adolesc Psychiatry. 2014;;53(8):

28 Status of Other Antidepressants Medication Bupropion* Selegiline Transdermal* Desvenlafaxine SR* Duloxetine* Controlled Study None Negative Failed Failed *Not FDA approved for MDD in children and adolescents DelBello MP, et al. J Child Adolesc Psychopharmacol. 2014;;24(6): ;; Emslie GJ, et al. J Child and Adol Psychopharmacol. 2014;;24(4): ;; Atkinson SD, et al. J Child and Adol Psychopharmacol. 2014,24(4):

29 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 *Not FDA approved for MDD in children and adolescents Pathak S, et al. J Child Adolesc Psychopharmacol. 2005;;15(4):

30 Treatment Resistant Depression Algorithm SSRI* fluoxetine/escitalopram If no response maximum dose, minimum 8 wks Partial response Augment aripiprazole, lithium or bupropion Partial response Augment aripiprazole or lithium Alternate SSRI* fluoxetine/escitalopram/citalopram/sertraline Different class of antidepressant bupropion/venlafaxine/duloxetine/desvenlafaxine Newer Antidepressants Vilazodone, levominacipran, Vortioxetine If no response maximum dose, minimum 8 wks If no response maximum dose, minimum 8 wks Only fluoxetine and escitalopram are FDA approved for MDD in children and adolescents;; *Add CBT Hughes CW, et al. J Am Acad Child Adolesc Psychiatry. 2007;;46(6):

31 Box Warning on Antidepressants Increase risk of suicidal thinking and behavior (suicidality) in children and adolescents treated with antidepressants Applies to all antidepressants Revision Depression associated with increase in risk of suicide Monitor appropriately and observe closely for clinical worsening, suicidality or unusual changes in behavior FDA Revisions to Product Labeling Suicide Warning for Antidepressants in Children and Adolescents. October 2004, FDA website

32 Antidepressant Dose and Self-Harm Probability of No Self-Harm (Dose) Initiation Miller M, et al. JAMA Intern Med. 2014;;174(6): Days

33 Omega-3 Fatty Acids in Prepubertal Depression 28 children (ages 6 to 12 years) with first episode major depression randomized to Omega-3 (1000 mg/day;; contained 400 mg EPA and 200 mg DHA) or placebo for 16 weeks Groups Response Rate, % (>50% Reduction in CDRS) Remission, % (CDRS <29) Omega Placebo 0 0 DHA = docosahexaenoic acid Nemets H, et al. Am J Psychiatry. 2006;;163(6):

34 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 1 of them with fluoxetine (initially 20 mg/d and later 40 mg/d) Open-label rtms for 14 days (10 Hz, 2-second trains given 20 min per day) 3 (33%) were responders ( 30% reduction in CDRS-R) rtms = repetitive transcranial magnetic stimulation Bloch Y, et al. J ECT. 2008;;24(2):

35 Bright Light Treatment for Adolescent Depression 28 adolescents with mild depressive disorder Randomized cross-over trial 14 subjects placebo (50 lux) for 1 hr in morning daily for 1 week then bright light therapy (2500 lux) for 1 week 14 subjects bright light (2500 lux) then placebo (50 lux) Results Significant improvement in BDI scores (depressive symptoms) Salivary melatonin was higher for the treatment than for the placebo group BDI = Beck Depression Inventory Niederhofer H, et al. Int J of Psychiatry in Clin Pract. 2012;;16(3):

36 Exercise for Adolescent Depression 13 adolescents with depression with low level of physical activity 12 week intervention 15 supervised exercise sessions 21 independent sessions Outcome All participants completed protocol, actigraphy verified 81% adherence Significant decrease in depression mean baseline CDRS-R 49;; endpoint 29 Significant increases in exercise Dopp RR, et al. Depress Res Treat. 2012;;2012:

37 Adolescents Assessments of Depression Treatment National Survey on Drug Use and Health Adolescents with past-year major depressive episode Treatment Helpful Extremely A Lot Some A Little Not At All Counseling (n = 2000) 10% 22% 25% 24% 20% Medication + Counseling (n = 1300) 17% 30% 22% 16% 15% Edlund MJ, et al. Psychiatric Services. 2015;;66(10):

38 SPARX (Smart, Positive, Active, Realistic, X-factor thoughts) Interactive fantasy game delivers CBT for depression Adolescent chooses an avatar and tries to restore balance in a fantasy world dominated by GNATS (Gloomy Negative Automatic Thoughts) Seven Modules Level 1: Cave Province Finding Hope Level 2: Ice Province Being Active Level 3: Volcano Province Dealing with Emotions Level 4: Mountain Province Overcoming Problems Level 5: Swamp Province Recognizing Unhelpful thoughts Level 6: Bridgeland Province Challenging Unhelpful Thoughts Level 7: Canyon Province Bringing it All Together Merry, SN et al. BMJ. 2012,344:e2598.

39 Computerized CBT for Depressed Adolescents 187 adolescents with depressive symptoms randomized to computerized CBT (SPARX) or counseling (treatment as usual) Results Similar reduction in CDRS-R scores between SPARX (10.3) and TAU (7.6) Similar response rates (SPARX:66%;; TAU:58%) Remission rates higher in SPARX arm (44% vs 27%) Merry, SN et al. BMJ. 2012,344:e2598.

40 Sparx Free online open to New Zealand residents only Search Sparx on YouTube SPARX YouTube Channel Merry, SN et al. BMJ. 2012,344:e2598.

41 Depression Resources American Academy of Child & Adolescent Psychiatry Facts for Families Depression Resource Center AACAP & APA Medication Guide FDA Website formationbydrugclass/ucm htm Antidepressant Use in Children & Adolescents Black Box Information

42 Clinical Connections Major depression is the leading cause of disabilityadjusted live years lost in adolescents Comorbid disorders are common in children and adolescents with major depression There is an increased risk of suicidal thinking and behavior (suicidality) in children and adolescents treated with antidepressants Consider all available evidence-based treatment options for adolescents with major depression 1

43 Call to Action Integrate a depression screening tool in your management of children and adolescents and consider all evidence-based treatment options 1

44 #CHAIR2016 Questions Answers &