Juvenile Depression.

Transcription

1 Juvenile Depression Karen Dineen Wagner, MD, PhD Titus Harris Chair Professor and Chair Department of Psychiatry & Behavioral Sciences University of Texas Medical Branch Galveston, Texas

2 Disclosure (Past 12 Months) Dr Wagner has received honoraria from UBM Medica, Nevada Psychiatric Association and American Society of Clinical Psychopharmacology.

3 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

4 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 Age Total Severe Impairment Male % % MDD or Dysthymia Merikangas KR et al. J Am Acad Child Adolesc Psychiatry. 2010; 49:

5 Screening for Adolescent Depression Comparison of Patient Health Questionnaire 9-item (PHQ-9) vs 2-item (PHQ-2) PHQ-9 items Interest or pleasure* Depressed* Sleep Fatigue Appetite PHQ-9 was more valid (AUC 93% vs 87%) Sensitivity 90% Psychomotor retardation/agitation Concentration Self esteem Suicidality Specificity 87% * PHQ-2 items Allgaier AK et al. Dep and Anx 2012; 29:

6 Screening Items for Adolescents History of concussion 3.3-fold increased risk for depression Parental job loss 2-3% increase in suicide-related behaviors Parental suicide attempt 5- fold increased risk for suicide attempt in offspring Brent DA et al. JAMA Psychiatry 2014 Dec 30. doi: /jamapsychiatry ; Chrisman SPD & Richardson LP. J Adolesc Health 2014; 54: ; Gassman-Pines A et al. Am J of Public Health 2014;104(10):

7 Major Depression in Youth and Cardiovascular Disease American Heart Association Scientific Statement Major Depression in Youth Moderate risk condition for Accelerated atherosclerosis Early cardiovascular disease Goldstein BI et al. Circulation published online Aug 10.

8 Top Ten Causes of DALYs Lost Among Adolescents DALYs Disability-adjusted live years lost World Health Organization 2014, Health for The World s Adolescents,

9 Top Ten Causes of Death Among Adolescents World Health Organization 2014, Health for The World s Adolescents,

10 Prevalence of Suicidal Behavior Greater in Depressed Adolescents National Comorbidity Survey of 6483 adolescents Lifetime Prevalence (%) Suicidal ideation 12.1 Suicidal plans 4.0 Suicide attempts 4.1 Ideation (%) (n=717) Plan (%) (n=203) Attempt (%) (n=196) MDD/Dysthymia Nock MK et al. JAMA Psychiatry 2013; 70:

11 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 non-mood disorder Melvin GA et al. J Affective Disorders 2013, 151:

12 FDA Approval for Acute Treatment of Major Depressive Disorder Medication Ages Fluoxetine (3 studies) 8-17 Escitalopram (1 study) Prozac Prescribing Information. Lexapro Prescribing Information. Emslie GJ et al. Arch Gen Psychiatry, 1997; 54: ; Emslie GJ et al, J Am Acad Child Adolesc Psychiatry, 2002;41: Treatment for Adolescents with Depression Study (TADS) Team. JAMA, 2004; 292: Emslie GJ et al: J Am Acad Child Adolesc Psychiatry, 2009; 48:

13 * On primary outcome measure ** Individual trials negative (March et al, 2004; Wagner et al, 2003; 2004 Berard et al, 2006; Keller et al, 2001; Emslie et al, 2006; 2007; Wagner et al, 2006; Rynn et al, 2002; Von Knorring et al, 2006; Rynn et al, 2002; Other Controlled Pediatric Depression Trials Positive* studies Medication Ages Number of Studies Citalopram Sertraline (a priori pooled analysis)** Negative* studies Citalopram Escitalopram Paroxetine Mirtazapine Nefazadone Venlafaxine

14 Meta-analysis of Antidepressant Trials Depression in Youth Response Rates Antidepressants 61% Placebo 50% Bridge JA et al, JAMA 2007; 297:

15 CDRS-R Importance of Early Response: Reduction in CDRS-R (Remitters vs. Non-Remitters) Non-Remitters Remitters Week LnWeek: P<0.001 Remission: P=0.06 Remission*LnWeek: P<0.001 Vitiello B et al. J Clin Psychiatry. 2011;72(3):

16 Responders Responders Maintenance Treatment for Adolescent Depression Acute Phase Sertraline (n=93) Continuation Phase Sertraline (n=51) 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 Cheung A et al. J Child Adolesc Psychopharmacol. 2008;18:

17 Treatment of Adolescent Depression Study 439 adolescent outpatients with major depression Randomized to 12 weeks 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:

18 Response Rates in Treatment for Adolescents with Depression Study (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 Treatment for Adolescents with Depression Study (TADS) Study Team. Arch Gen Psychiatry. 2007;64: ; Kennard BD et al. Am J Psychiatry. 2009:166:

19 Treatment of SSRI-Resistant Depression in Adolescents Trial 334 adolescents with major depression who failed to respond to 8 weeks of SSRI Randomized to 12 weeks of: Different SSRI Different SSRI + CBT Switch to venlafaxine Switch to venlafaxine plus CBT SSRI, selective serotonin reuptake inhibitor Brent D et al. JAMA. 2008;299:

20 % Responders Clinical Response by Treatment Group (CGI 2 and decrease CDRS-R 50%) * SSRI Venlafaxine No CBT CBT MED, medical intervention Brent D et al. JAMA. 2008;299: *P=0.02

21 Adverse Events Diastolic blood pressure, mm Hg a SSRI Venlafaxine Baseline Week 12 Baseline Week Heart rate, bpm b SSRI Venlafaxine N=168 N=166 Skin c 2% 8% a Venlafaxine vs SSRI: t=2.88; P=0.004; c By medication: χ²=6.69, P=0.01 Bpm, beats per minute Brent DA et al. JAMA. 2008;299(8): b Venlafaxine vs SSRI: t=3.41; P=0.001

22 Anhedonia Anhedonia was the depressive symptom most associated with poorer recovery in TORDIA Compared to irritability, more severe outcomes Greater illness severity Higher suicidality Greater episode duration Greater number of major depressive episodes Gabbay V et al. J Child Adol Psychopharm, 2015, 25, McMakin DL et al. J Am Acad Child and Adoles Psychiatry. 2012;51:

23 Active Ingredients in CBT Variable Adjusted Odds of Response, % >9 sessions 2.5 Social Skills 2.6 Problem Solving 2.3 Kennard BD et al. J Consult Clin Psychol. 2009;77(6):

24 Co-Rumination and Co-Problem Solving in Depressed Adolescents ** * * *p<.05; **p<.01 Waller JM et al. J Am Acad Child Adolesc Psychiatry 2014; 53:

25 Bupropion No controlled trials for pediatric depression Open trial of bupropion SR for 11 depressed adolescents: Response Rate (CGI-I 2) 73% Open trial of bupropion SR augmentation of SSRIs for 23 depressed adolescents: 65% of patients improved SR, sustained release Glod CA et al. J Child and Adolescent Psychiatric Nursing. 2003,16: ; Yeghiyan M et al. Augmentation of SSRIs with bupropion in treatment-resistant depression in adolescents. Annual Meeting American Psychiatric Association. May 17-22, San Francisco, California. Abstract No. NR415.

26 Selegiline Treatment for Adolescent Depression 308 adolescents with major depression Randomized to selegiline transdermal system flexible dosing (6 mg/24h, 9 mg/24h, or 12 mg/24h) or placebo CDRS-R EMSAM Placebo Baseline Endpoint EMSAM: selegiline transdermal system. Delbello MP et al, J Child Adols Psychopharm 2014;

27 Mean Change CDRS-R Mean Change CDRS-R Controlled Trials of Duloxetine for Pediatric Major Depression Fixed Dose Weeks Flexible Dose Weeks Emslie GJ et al. J Child and Adol Psychopharm 2014; 24: ; Atkinson SD et al. J Child and Adol Psychopharm 2014, 24: ;

28 Desvenlafaxine SR for Pediatric Depression 340 outpatients, ages 7 to 17 years with major depression Double-blind, randomized to desvenlafaxine SR (weight based dosing 35mg/day), fluoxetine (20mg/day), and placebo Failed Study Desvenlafaxine SR and fluoxetine not significantly superior to placebo Pfizer Press Release. ase_formulation_in_pediatric_patients_with_major_depressive_disorder. Accessed June 11, 2015

29 Newer Antidepressants No efficacy data available in pediatric depression Vilazodone L-methylfolate Ketamine Levomilnacipran Vortioxetine

30 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 Pathak S et al. J Child Adoles Psychopharmacol. 2005;15:

31 Partial response Augment aripiprazole, lithium or bupropion Partial response Augment aripiprazole or lithium Treatment Resistant Depression Algorithm SSRI* fluoxetine/escitalopram If no response maximum dose, minimum 8 wks Alternate SSRI* fluoxetine/escitalopram/citalopram/sertrali ne If no response maximum dose, minimum 8 wks Different class of antidepressant bupropion/venlafaxine/duloxetine/desvenlafaxin Newer Antidepressants Vilazodone, levominacipran, Vortioxetine e If no response maximum dose, minimum 8 wks * Add CBT

32 Efficacy vs. Suicidal Risk of Antidepressants in Pediatric Patients Meta-analysis of 27 trials of pediatric major depression Suicidal Ideation/attempts Antidepressants 3% Placebo 2% (Bridge JA et al, JAMA 2007;297: )

33 Comparison of Antidepressants and Suicide Attempts in Youth Retrospective cohort study of 36,842 youth enrolled in Tennessee Medicaid who were new users of antidepressants 419 medically treated suicide attempts Medication Adjusted Relative Risks Fluoxetine 1 Sertraline 0.97 Paroxetine 0.80 Citalopram 0.92 Escitalopram 0.80 Venlafaxine 0.80 Multiple SSRIs only 1.70 Cooper WO et al. Pediatrics 2013, doi: /peds

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

35 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):

36 Vitamin D Supplementation for Adolescent Depression Case-series of 48 depressed adolescents with serum 25 (OH) Vitamin D levels below 60nmol/L Vitamin D 3 supplementation 4000 IU daily for 1 month 2000 IU daily for 2 months Results Mean 25 (OH) Vitamin D Level: baseline 41 nmol/l; endpoint 91 nmol/l Adolescents reported improved well-being and improved depressive symptoms Hӧgberg G et al. Acta Paediatrica 2012; 101:

37 CDRS Adjunctive Vitamin C for Pediatric Major Depression + Fluoxetine (10-20mg/day) (n=12) * Amr M et al Nutrition Journal 2013; 12:31

38 Electroconvulsive Therapy No controlled data Retrospective study of 12 adolescents 33% had a 60% improvement in depressive symptoms Hegeman JM et al. Tijdschr Psychiatr. 2008;50:23-31.

39 Repetitive Transcranial Magnetic Stimulation 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% reductions in CDRS-R) rtms, repetitive transcranial magnetic stimulation Bloch Y et al. J ECT. 2008;24:

40 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 depressive symptoms (BDI scores) Salivary melatonin was higher for the treatment than for the placebo group Niederhofer H & Von Klitzing K. Int J of Psychiatry in Clin Pract 2012; 16:

41 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 Significant decrease in depression (mean baseline CDRS-R 49; endpoint 29) Dopp RR et al. Depression Research and Treatment 2012; doi: /2012/257472

42 Family-Based Interpersonal Psychotherapy for Depressed Children (ages 7-12) Family-Based Interpersonal Psychotherapy (FB-IPT) Addresses parent-child conflict and interpersonal impairment Parents involved in 14 weekly sessions Client Centered Therapy Supportive, nondirective Depressive Symptoms CCT (n=13) Social Impairment CCT (n=13) FB-IPT (n=29) FB-IPT (n=29) Dietz LJ et al. J Am Acad Child Adolesc Psychiatry 2015, 54:

43 Adolescents Assessments of Depresion 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) Medication + Counseling (n=1300) 10% 22% 25% 24% 20% 17% 30% 22% 16% 15% Edlund MJ et al. Psychiatric Services 2015;66(10):

44 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. doi: /bmj.e2598.

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47 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%) Merry SN et al. BMJ. 2012, 344:e2598. doi: /bmj.e2598.

48 Sparx Free online open to New Zealand residents only Search Sparx on YouTube SPARX YouTube Channel

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

50 Medication Sheets