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Juvenile Depression
Karen Dineen Wagner, MD, PhDProfessor and Chair
Titus Harris ChairHarry K. Davis Professor
Department of Psychiatry & Behavioral Sciences
University of Texas Medical Branch
President, American Academy of Child and Adolescent Psychiatry
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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
Sex Age Total Severe
Impairment
Female
%
Male
%
13-14 15-16 17-18 %
MDD or Dysthymia 15.9 7.7 8.4 12.6 15.4 11.7 8.7
Merikangas KR et al. J Am Acad Child Adolesc Psychiatry. 2010; 49:980-989
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Top Ten Causes of Death Among Adolescents
World Health Organization 2014, Health for The World’s Adolescents, www.who.int/adolescent/second-decade
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Long-Term 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; 151:298-305
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FDA Approval for Acute Treatment of Major
Depressive Disorder
Medication Ages
Fluoxetine (3 studies) 8-17
Escitalopram (1 study) 12-17
Prozac Prescribing Information. Lexapro Prescribing Information.
Emslie GJ et al. Arch Gen Psychiatry. 1997; 54:1031–1037; Emslie GJ et al, J Am Acad Child Adolesc Psychiatry.
2002;41:1205–1215. Treatment for Adolescents with Depression Study (TADS) Team. JAMA. 2004; 292:807–820.
Emslie GJ et al: J Am Acad Child Adolesc Psychiatry. 2009; 48:721–729.
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Other Controlled Pediatric Depression Trials
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;
www.fda.gov/cder/foi/esum/2004/20152s032_serzone)
Medication Ages
Positive
studies
Citalopram 7-17
Sertraline
(a priori pooled analysis)
6-17
Negative
studies
Citalopram 13-18
Escitalopram 6-17
Mirtazapine
Nefazadone
Paroxetine
Venlafaxine
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Meta-analysis of Antidepressant Trials
Depression in Youth
Response Rates
Antidepressants 61%
Placebo 50%
Bridge JA et al, JAMA. 2007; 297:1683-1696.
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Antidepressant Treatment Duration in Children
and Adolescents
▪ Review of electronic prescription records of 8,837 children
and adolescents with major depression prescribed
antidepressants
▪ Rate of 6-month antidepressant use
▪ 46%
▪ Reasons for discontinuation
▪ More days without medication between first prescription
and refill
Bushnell GA, Stürmer T, White A, Pate V, Swanson SA, Azrael D, Miller M. Journal of affective disorders. 2016 May 15;196:138-47
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Treatment of Adolescent Depression Study
(TADS)
▪ 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;292:807-820.
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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;64:1132-1144; Kennard
BD et al. Am J Psychiatry. 2009:166:337-344.
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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;299:901-913.
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Clinical Response by Treatment Group
(CGI ≤2 and decrease CDRS-R ≥50%)%
Res
ponder
s
*P=0.02
*SSRI
Venlafaxine
No CBT
CBT
MED, medical intervention
Brent D et al. JAMA. 2008;299:901-913.
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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. 2003,16:123-130; Yeghiyan M et al. Augmentation of
SSRIs with bupropion in treatment-resistant depression in adolescents. Annual Meeting American Psychiatric
Association. May 17-22, 2003. San Francisco, California. Abstract No. NR415.
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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
EMSAM: selegiline transdermal system. Delbello MP et al, J Child Adols Psychopharm. 2014; 24:1-7
CDRS-R EMSAM® Placebo
Baseline 56.7 57.9
Endpoint 35.4 36.4
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Controlled Trials of Duloxetine for
Pediatric (7-17 years) Major Depression
Emslie GJ et al. J Child and Adol Psychopharm. 2014; 24: 170-179; Atkinson SD et al. J Child and Adol Psychopharm. 2014, 24:180-189;
0 1 2 4 7 10
Weeks
0 1 2 4 7 10
Weeks
Mean C
hange C
DR
S-R
Me
an C
hange C
DR
S-R
Fixed Dose
Flexible Dose
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Desvenlafaxine Treatment for Pediatric
(7-17 years) Major Depression
Weihs KL et al. J Child and Adolescent Psychopharm. 2017. [Epub ahead of print]
Fluoxetine 20mg
Desvenlafaxine
25, 35 or 50mg
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Vortioxetine: Pharmacokinetics and Safety
▪ 48 youth, ages 7-17 years with depression and anxiety
disorders
▪ Open-label study of vortioxetine 5mg, 10mg, 15mg or 20mg
for 14-20 days
▪ Higher doses titrated over 2-6 days
▪ Findings
• PK of vortioxetine concentration proportional to dose
Findling RL, et al. J of Child Adolesc Psychiatry. 2017; 20:1-9.
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Newer Antidepressants in Pediatric Depression
Medication Status
Vilazodone Pediatric MDD study completed
Levomilnacipran Adolescent MDD study in progress
Ketamine Adolescents with treatment
refractory MDD study in progress
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Treatment Resistant Depression Algorithm
If no response maximum dose, minimum 8 wks
Partial response
SSRI*fluoxetine/escitalopram
Alternate SSRI*fluoxetine/escitalopram/citalopram/sertraline
Augment aripiprazole,
lithium or bupropion
Different class of antidepressantbupropion/venlafaxine/duloxetine/ desvenlafaxine
Partial response
Newer Antidepressantsvortioxetine, vilazodone, levominacipran
If no response maximum dose, minimum 8 wks
Augment aripiprazole
or lithiumIf no response maximum dose, minimum 8 wks
* Add CBT
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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-3 70 40
Placebo 0 0
DHA, docosahexaenoic acid
Nemets H et al. Am J Psychiatry. 2006;163(6):1098-1100.
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Repetitive Transcranial Magnetic Stimulation
(rTMS) for Treatment Resistant Depression
▪ 9 adolescents open-label rTMS for 20 treatments
▪ Response rate 33% (≥ 30% reduction; CDRS-R)
▪ 8 adolescents adjunctive rTMS (added to SSRI) for 30
treatments
▪ Significant reduction in baseline CDRS-R
▪ Three year follow-up of 9 adolescents treated with rTMS
▪ Maintained clinical improvement
Bloch Y et al. J ECT. 2008;24:156-159; Wall CA, et al. The Journal of clinical psychiatry. 2011 Sep 15;72(9):1263-9; Mayer G et al.
The journal of ECT. 2012 Jun 1;28(2):84-6.
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AACAP Presidential Initiative
Increase awareness of and screening for depression in
children and adolescents
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Screening for Depression in
Children and Adolescents
▪ Recommendation from US Preventative Task Force
▪ Screening for major depressive disorder in adolescents
ages 12 to 18 years
(PHQ-A highest positive predictive value)
▪ 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; 164:360-366.
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Components of AACAP Presidential Initiative
▪ Education of parents and youth about depression
▪ Symptoms, course, treatment
▪ AACAP online Depression Resource Center
▪ Up-to-date, evidence-based information
▪ Collaboration with national organizations dealing with
children’s mental health
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AACAP Presidential Initiative Projects
▪ Clinical Practice Guideline on Assessment and Treatment of
Depression in Children and Adolescents
▪ Update Parent Medication Guide on Depression
▪ Online Depression Resource Center
▪ Update existing materials
▪ Create a section for teenagers
(Continued)
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AACAP Presidential Initiative Projects
▪ JAACAP Connect Call for Papers
▪ Programs with depression screening and referral system
▪ Child and Adolescent Psychiatric Clinics
▪ Special populations
(Continued)
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AACAP Presidential Initiative Projects
▪ JAACAP submissions on depression
▪ Master clinician reviews
▪ Clinical perspectives
▪ Case conferences
▪ AACAP Annual meeting
▪ Request for submissions on depression