psychopharmacologic approaches to depression in … · 2020. 10. 15. · tordia: insomnia •...

PSYCHOPHARMACOLOGIC APPROACHES TO DEPRESSION IN CHILDREN AND ADOLESCENTS

Learning Objectives

• Describe the evidence for selective serotonin reuptake inhibitors (SSRIs) in youth with depressive disorders

• List predictors of treatment response in adolescents with SSRI-resistant major depressive disorder

• List specific patient characteristics that may guide treatment selection in adolescents with major depressive disorder

Off-Label Medication Use

Dr. Strawn does intend to discuss the use of off-label/unapproved use of drugs.

AdolescencePreschool School-AgeAge 7Age 4 Puberty

Irritability3

Moodiness3

Loss of interest3

Depressed mood, lack of concentration, insomnia, suicidal ideation

Somatic complaints

Increase in suicide attempts and suicide completion

Hypersomnia (increases with age)2

Ryan et al. The Clinical Picture of Major Depression in Children & Adolescents. Arch Gen Psychiatry 1987;44:854-61; Luby et al. Modification of DSM-IV Criteria for Depression in Depressed Preschool Children. Am J Psychiatry 2003;160:1169-72; Lewinsohn et al. Major depression in community adolescents: age at onset, episode duration, and time to recurrence. J Am Acad Child Adolesc Psychiatry 1994;33:809-18.

Weight loss (increases with age)1

Clinical Aspects of Depression Vary

Delusions

EDSP: Incidence and Onset of Depression

Beesdo et al. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch Gen Psychiatry 2010;67:47-57.

Treatment of Depression in Youth• Multimodal treatment—psychotherapy and pharmacotherapy

• Psychotherapies • cognitive behavioral, • supportive, • group, • family therapy, • social skills training, and • psychodynamic

Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press);Birmahar et al. Practice Parameter for the Assessment and Treatment of Children and Adolescents with Depressive Disorders. J Am Acad. Child Adolesc Psychiatry 2007;46:1503-26.

• Pharmacotherapies• SSRIs are 1st line

psychopharmacologic treatment for children with depression

• SNRIs are also being used by many clinicians, but data are limited

• No positive trials for MAOIs• No positive trials for TCAs

Treatment of Adolescent Depression Study

Treatment Week

Adj

uste

d M

ean

Chi

ldre

n’s

Dep

ress

ion

Rat

ing

Scal

e Sc

ore

45

60

306 120

PlaceboCBT AloneFluoxetine alone

Fluoxetine + CBT

March et al. JAMA 2004;292:807-20; Emslie et al. J Am Acad Child Adolesc Psychiatry 2006;45:1440–55.

• Fluoxetine + CBT > placebo, p=.001 • Fluoxetine + CBT > fluoxetine, p=.02 • Fluoxetine > CBT alone, p=.01 • Response rates:

• fluoxetine + CBT, 71%; • fluoxetine alone, 61%; • CBT alone, 43%; • placebo, 35%

Symptomatic Improvement in MDD

Tao et al. J Child and Adolesc Psychopharmacology 2010.

Fluoxetine Treatment Week

Mea

n S

cale

Sco

re

1

2

0 6 8 10 120 1 2

Morbid ThoughtsAnhedoniaObserved Depression

Reported Depression

3 4

3

4

Time Course of Response and Side Effects

Duration of antidepressant treatment

Weight gain (if applicable)

Monoamine levels

activation

Symptoms

Receptor sensitivity

SSRI Response: How long to wait?

Varigonda et al. JAACAP 2015;54(7):557-64; Strawn et al. JAACAP 2018;57(4):235-44.

Impr

ovem

ent i

n D

epre

ssiv

e Sy

mpt

oms

0 2 4 6 8 10

0

-0.1

-0.2

-0.3

-0.4

-0.5

Week

Titration Strategies Based on RCTs

Initial 5 mg 25 mg 5 mg

Week 1 10 mg 50 mg 20 mg




Optional increases






Week 10 20 mg 150 mg 40 mg

fluoxetineescitalopram sertraline

Age 7–11

Titration Strategies Based on RCTs

Initial 5 mg 25 mg 10 mg





Optional increases






Week 10 20 mg 200 mg 60 mg

fluoxetineescitalopram sertraline

Age 12–17

Rationale for Focus on Adolescents WithTreatment-Resistant Depression (TRD)

• Remission rate around 30%• TRD associated with increased

morbidity and development of chronic depression

• Identify the next, best steps for SSRI-resistant depression in adolescents

Brent et al. Treatment of Resistant Depression In Adolescents. JAMA 2008;299(8):901-13.Strawn and Walkup. The quest to identify the best treatment for pediatric depression. Lancet Psychiatry 2020 (in press).Strawn et al. Treatment Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance. J Child Adolesc.Psychopharm 2020 (in press).

Defining “Adequate” SSRI Treatment

• > 8 weeks

• Last 4+ weeks at equivalent of 40 mg of fluoxetine

• May use 20 mg equivalent if unable to tolerate higher dose

Fluoxetine20 mg

Fluoxetine40 mg

Brent D et al. JAMA 2008;299(8):901-13.

Fluoxetine40 mg

SSRI Non-responders(>2 mos of tx)

Week0

Week12

Wk-3

Brent D et al. JAMA 2008;299(8):901-13.

N=334Age: 12–18 years Dx: MDD + no response to 2-month initial SSRI

Primary Outcome: CGI-I <2 + >50% decrease in CDRS-R and dCDRS-R.

SNRI + CBTVenlafaxine XR

SNRIVenlafaxine XR

SSRI + CBTCitalopram + CBTParoxetine + CBTFluoxetine + CBT

SSRICitalopramParoxetineFluoxetine

TORDIA Design

What did they find?

Treatment Week

40

60

20 6 120

SSRIVenlafaxine

30

50

CD

RS

Scor

e

Treatment Week

2

4

6 120

1

3

Antidepressant withoutCBTAntidepressant + CBT

Clin

ical

Glo

bal I

mpr

essi

on

Scal

e—Se

verit

y

5

Brent D et al. JAMA 2008;299(8):901-13.

TORDIA: Primary Findings


Impr

ovem

ent i

n D

epre

ssiv

e Sy

mpt

oms

Mills, Croarkin Strawn. Under review 2020.


Impr

ovem

ent i

n D

epre

ssiv

e Sy

mpt

oms

Mills, Croarkin Strawn. Under review 2020.

p=0.01

Anhedonia and Treatment Response

• Only symptom that predicts lack of remission when controlling for others

• Strongest predictor of fewer depression free days

• Treatment did not target positive affect (only 1.5 sessions of behavioral activation)

• May need to more specifically target behavioral activation

anhedonia

Drug and Alcohol Use in TORDIA

Goldstein BI et al. J Am Acad Child Adolesc Psychiatry 2009;48(12):1182-92.

No response

Response

Subs

tanc

e U

se S

ever

ity

Time (weeks)

Plasma Concentration and Response

Sakolsky DJ et al. J Clin Psychopharmacol 2011;31(1):92-7.

01020304050607080

VEN FLX/CIT FLX CIT PAR

≥ GM<GM

P=.04

P=.07P=.005

Adolescent SSRI Exposure

Ramsey et al. Gene-Based Dose Optimization in Children. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.

16-year-old female

14-year-old female

Cytochrome P450 Enzymes and Pharmacokinetics in Adolescents

Ramsey et al. Annu Rev Pharmacol Toxicol 2020;60:4.1–4.21.

Pediatric Escitalopram and CYP2C19

Strawn, Poweleit, Ramsey. CYP2C19-guided escitalopram and sertraline dosing in pediatric patients: a pharmacokinetic modeling study. J Child Adol Psychop 2019;29(5):340-7.

Intermediate metabolizerPoor metabolizer

Normal metabolizerRapid metabolizerUltrarapid metabolizer

Phenotype Equivalent dose

Poor metabolizer

10 mg

Intermediatemetabolizer

15 mg

Normalmetabolizer

20 mg

Rapid metabolizer

25 mg

Ultrarapidmetabolizer

30 mg

Pediatric Sertraline and CYP2C19

Strawn JR et al. J Child Adol Psychop 2019;29(5):340-7.

Intermediate metabolizerPoor metabolizer

Normal metabolizerRapid metabolizerUltrarapid metabolizer

Phenotype Equivalent dose

Poor metabolizer

50 mg

Intermediatemetabolizer

125 mg

Normalmetabolizer

150 mg

Rapid metabolizer

175 mg

Ultrarapidmetabolizer

225 mg

TORDIA: Self-Harm in High Ideators

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

SSRI VLX

LowHigh

p=0.75

p=0.02

Adapted from G. Emslie. Annual Meeting of the American Academy of Child & Adolescent Psychiatry 2012.

TORDIA: Treatment and Suicidal Events

Brent DA et al. Am J Psychiatry 2009;166:418–26.

TORDIA: Early Response

20253035404550556065

0 6 12 24

CD

RS-

R

Week

Non-Remitters

Emslie GJ et al. Am J Psychiatry. 2010;167(7):782-91.

TORDIA: Early Response

20253035404550556065

0 6 12 24

CD

RS-

R

Week

Non-RemittersRemitters

Emslie GJ et al. Am J Psychiatry 2010;167(7):782-91.

TORDIA: Insomnia• Trazodone-treated patients, 6x < likely

to respond than patients who did not receive any soporific (p=0.001)

• Trazodone-treated patients 3x more likely to self-harm (OR=3, p=0.03)

• No patient receiving trazodone + paroxetine or fluoxetine responded (0/13)

• Patients treated with other soporifics responded similarly to those who received no sleep medication (60% vs. 50%)

Shamseddeen W et al. J Child Adolesc Psychopharmacol 2012;22(1):29-36.

Trazodone mCPP

TORDIA: Insomnia• Trazodone-treated patients, 6x < likely

to respond than patients who did not receive any soporific (p=0.001)

• Trazodone-treated patients 3x more likely to self-harm (OR=3, p=0.03)

• No patient receiving trazodone + paroxetine or fluoxetine responded (0/13)

• Patients treated with other soporifics responded similarly to those who received no sleep medication (60% vs. 50%).

ParoxetineFluoxetine

2D6

Trazodone mCPP

mCPP

Shamseddeen W et al. J Child Adolesc Psychopharmacol 2012;22(1):29-36.

TORDIA Take Homes

• Medication + Therapy > Medication (NNT=7)• Venlafaxine

• more side effects• less efficacy than another SSRI as 2nd line

• Medication dose/exposure is IMPORTANT• COMBO >> MED with comorbidity• Poorer response:

• substance use, • family conflict, • sleep difficulties

When to Adjust Treatment in Adolescent MDD

Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry 2019;58(1):80-91.

IPT-AEarly decision

>20% reduction

<20% reduction

IPT-AEarly decision

>20% reduction Continue IPT-A

IPT-A Frequency

<20% reduction

Fluoxetine


Gunlicks-stoessel M et al. J Am Acad Child Adolesc Psychiatry. 2019;58(1):80-91.

IPT-AEarly decision


IPT-A Frequency

<20% reduction

Fluoxetine


IPT-ALate decision

>40% reduction

<40% reduction


IPT-AEarly decision


IPT-A Frequency

<20% reduction

Fluoxetine


IPT-ALate decision

>40% reduction

Continue IPT-A

IPT-A Frequency

<40% reduction

Fluoxetine


TMS in Adolescents With Treatment-Resistant Depression

Croarkin et al. In preparation.

• Multi-site, N=103• Age 12-21, ATR >1• No concurrent medication

Left dorsolateral prefrontal cortex stimulation, 5 days/week

• It has been the first medication trial

• It has been poorly tolerated• There is <25% improvement • There is more time to wait (i.e.,

less functional impairment)• There may be drug interaction• There may be adherence

concerns

• The initial antidepressant was well tolerated

• There is a partial response to the initial agent (>25% improvement)

• There is less time to wait for a response (e.g., more functional impairment)

Switching vs. Augmentation

Switching Medications

• Direct switch: stop first antidepressant and start new antidepressant

Keks N et al. Aust Prescr 2016;39(3):76-83; Stahl. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide. 4th Edition.



• Taper and switch immediately:gradually taper the first antidepressant and start the new antidepressant immediately after discontinuation





• Taper and switch after a washout: gradually withdraw the first antidepressant then start the new antidepressant after a wash out period






• Taper and switch after a washout: gradually withdraw the first antidepressant then start the new antidepressant after a wash out period

• Cross-tapering: taper or maintain the first antidepressant while beginning the new antidepressant

Conclusions• Treatment should be multimodal• Consider augmentation EARLY• Changing antidepressants and/or adding other treatment

strategies leads to treatment response in 50–60% of patients with treatment-refractory depression

• In patients who fail to respond to an SSRI, a second SSRI trial is warranted rather than a switch to an SNRI

• Medication dose (and exposure) is important in improving outcomes!

• Caution with venlafaxine, particularly those with suicidal ideation at the beginning of treatment

Posttest QuestionFollowing unsuccessful treatment with paroxetine and fluoxetine, a 15-year-old girl, who meets DSM-5 criteria for major depressive disorder, is prescribed extended-release venlafaxine which is initiated at 37.5 mg daily and titrated to 150 mg daily for 8 weeks. She has had minimal improvement in depressive symptoms. Which of the following represents a significant clinical consideration?1. Venlafaxine treatment may increase her likelihood of treatment-emergent

suicidality2. Addition of cognitive-behavioral therapy is unlikely to confer any significant

benefit3. Her likelihood of clinical improvement is directly related to her serum

venlafaxine concentration4. Addition of trazodone to manage her initial insomnia may increase her

likelihood of remission

A 13-year-old boy meets DSM-5 criteria for major depressive disorder and has been treated with paroxetine 40 mg daily for 8 weeks. He has had minimal improvement in depressive symptoms. Which of the following represents an evidence-based treatment option?

1. Continue for an additional 4 weeks at the current dose. 2. Discontinue paroxetine and begin duloxetine 30 mg qAM3. Discontinue paroxetine and begin citalopram 10 mg qAM4. Augment with buspirone 10 mg BID

Posttest Question

Higher blood levels of which of the following medications have been associated with a greater likelihood of improving in adolescents with treatment-resistant depression?

1. Venlafaxine2. Citalopram3. Fluvoxamine4. Duloxetine

Posttest Question

psychopharmacologic approaches to depression in … · 2020. 10. 15. · tordia: insomnia •...

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