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

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

Top Ten Causes of Death Among Adolescents

World Health Organization 2014, Health for The World’s Adolescents, www.who.int/adolescent/second-decade

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

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.

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

Meta-analysis of Antidepressant Trials

Depression in Youth

Response Rates

Antidepressants 61%

Placebo 50%

Bridge JA et al, JAMA. 2007; 297:1683-1696.

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

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.

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.

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.

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.

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.

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

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

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

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.

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

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

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.

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.

AACAP Presidential Initiative

Increase awareness of and screening for depression in

children and adolescents

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.

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

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)

AACAP Presidential Initiative Projects

▪ JAACAP Connect Call for Papers

▪ Programs with depression screening and referral system

▪ Child and Adolescent Psychiatric Clinics

▪ Special populations

(Continued)

AACAP Presidential Initiative Projects

▪ JAACAP submissions on depression

▪ Master clinician reviews

▪ Clinical perspectives

▪ Case conferences

▪ AACAP Annual meeting

▪ Request for submissions on depression