Psychopharmacologic Consultant Neuronetics X · Strawn et al. Depression & Anxiety. 2015 |Locher,...

Jeffrey R. Strawn, MD 6/22/2019

1

Recent Advances in the Psychopharmacologic

Treatment of Pediatric Anxiety: Tailoring Treatments and

Enhancing OutcomesJeffrey R. Strawn, MD, FAACAP

Associate Professor of Psychiatry and PediatricsUniversity of Cincinnati

Cincinnati Children’s Hospital Medical Center

Disclosures of Potential ConflictsSource Research

FundingAdvisor/

ConsultantSpeaker’s Bureau Books, Intellectual

PropertyIn-kind

ServicesStock or Equity

Neuronetics X

Allergan X

Lundbeck X

National Institutes of Health (NIMH)

X

National Institutes of Health (NIEHS)

X

Springer Publishing X

UpToDate X

Assurex/Genesight

X X

CMEology X

Disclosure: Off Label Medication Use will be DiscussedThe following are FDA-approved antidepressants in children and adolescents

Class Medication Age (years)

SSRI

6 7 8 9 10 11 12 13-17

Citalopram NONEEscitalopram NONE MDD

Fluoxetine OCDNONE MDD

Fluvoxamine NONE OCD

Paroxetine NONE

Sertraline OCD

Vilazodone NONE

Vortioxetine NONE

SSNRI

Duloxetine GAD

Desvenlafaxine NONE

Venlafaxine NONE

Atypical Antidepressant

Bupropion NONE

Mirtazapine NONE

Trazodone NONE

Anxiety


2

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Variability in Treatment Response Current Approach: Assumptions


3

Precision Medicine Precision TxGen

Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Psychopharmacologic Treatment of Anxiety in Pediatric Patients

General Principles

Pediatric GAD: Fixed-Dose Sertraline

0 1 2 3 4 5 6 7 8 9Week

20

15

10

5

0

Hamilton

Anxiety Rating Scale

Rynn MA, Siqueland L, Rickels K. Placebo-controlled trial of sertraline in the treatment of children with generalized anxiety disorder. Am J Psychiatry. 2001;158(12):2008-14.

In most pediatric anxiety studies, SSRI/SNRI separates from placebo between week 2 and week 4


4

• Age– 6 to 17 years

• Randomization– Venlafaxine (N=157) or placebo

(N=163) for 8 weeks. • Primary outcome measure

– Composite score for GAD section of a modified version of the K-SADS for School-Age Children

• Results– Pooled analysis, venlafaxine

• Venlafaxine > placebo for decrease in K-SADS GAD score (–17.4 vs –12.7).

– CGI Response• venlafaxine > placebo (69% vs

48%).

Pediatric GAD: Venlafaxine XR

Rynn, et al. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am J Psychiatry. 2007;164(2):290-300.

Baseline 1 2 3 4 5 6 7 8

40

35

30

25

Raw

Sco

re o

n N

ine

Del

inea

ted

Item

s fo

r GAD

Fr

om C

olum

bia

K-SA

DS

Pediatric GAD: Duloxetine• Patients• 7-17 years of age

– Duloxetine, 12.6 ± 3 years– Placebo, 12.2 ± 3 years

• Inclusion– Moderate severity GAD

• Outcome– Change in PARS Severity for

GAD– Change in PARS (total)

Strawn, Prakash, Zhang, et al. A randomized, placebo-controlled study of duloxetine for the treatment of children and adolescents with generalized anxiety disorder. J Am Acad Child & Adolescent Psychiatry. 2015;54:283-93.

-12

-7

-2

3 Duloxetine (N=135)Placebo (N=133)

LS M

ean

Cha

nge

Week0 1 2 4 7 10 LOCF

-0.50.51.52.53.54.55.56.5

Weight (kg) Diastolic BP (mm Hg)Systolic BP (mm Hg) Pulse (bpm)

Duloxetine (N=135)Placebo (N=137)

Mea

n C

hang

e fro

m

Base

line

durin

g Ac

ute

Trea

tmen

t

Adolescent GAD: Escitalopram vs. Placebo

Strawn et al, 2019 (unpublished)

• Patients– 12-17 years of age

• Dosing– Forced-Flexible– 5 mg qAM x 2 days then 10 mg qAM x 7 days then 15

mg qAM until week 4 at which time escitalopramcould be increased to 20 mg qAM.

• Inclusion– Moderate severity GAD, no MDD– Stable psychotherapy

• Outcome– Change in PARS from baseline to endpoint– CGI-I and CGI-S

Baseline Characteristics Escitalopramn=26

Placebon=25

Age, years Mean (SD) 14.8 (1.7) 14.9 (1.6) Sex, n (%) Female 20 (77) 19 (76) Race, n (%) Asian 0 (0) 2 (8) Black & African American 1 (4) 1 (4) Caucasian 23 (88) 20 (80) Other 2 (8) 2 (8) IQ Score (SD) 106 (12) 105 (10) PARS Score Mean (SD) 18 (2) 17 (2) CDRS Score Mean (SD) 33(4) 32(6) Comorbidity Separation anxiety, n (%) 4 (15) 5 (20) Panic disorder, n (%) 13 (50) 15 (60) Agoraphobia, n (%) 7 (27) 7 (28) ADHD, n (%) 5 (19) 4 (16) Strawn et al, 2019 (unpublished)

−12

−8

−4

0

0 2 4 6 8Treatment Week

Cha

nge

in P

ARS

Scor

e

p=0.01p<0.001

p=0.002

p<0.001p<0.001

Adolescent GAD: Escitalopram vs. Placebo


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Guanfacine ER in Pediatric Anxiety• Dx: GAD, separation anxiety

disorder, social anxiety disorder.• No ADHD, no MDD, no BP• N = 83• Age 6-17 (mean: 12±3)• 1-6 mg/day, 3:1 randomization• 32 sites

Strawn JR, Compton S, Robertson B, Albano AM, Hamdani M, Rynn MA. J. Child & Adolesc. Psychopharm. 2017;27(1):29-37.

Predicting Treatment Response in Pediatric Anxiety

The Impact of Comorbidity

CAMS: Predictors of RemissionSocial Anxiety/Social Phobia & Age

Ginsburg et al. Remission After Acute Treatment in Children and Adolescents with Anxiety Disorders: Findings From the CAMS. Journal of Consulting and Clinical Psychology. 2011;79(6):806–813

0102030405060708090 No SoP

SoP

Rem

issi

on b

y C

GI-S

Sco

re (%

)

01020304050607080

Age 7-11 yearsAge 12-17 years

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers


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Predicting Treatment Response in Pediatric Anxiety

The Impact of Metabolism

Citalopram & EscitalopramMetabolism and Outcome Relevance

CitalopramN-oxide

2C193A42D6

r-desmethyl-citalopram

s-desmethyl-citalopram

2C193A42D6

s-didesmethyl-citalopram

r-didesmethyl-citalopram

2D6

2D6

2D6Amineoxidase

Amineoxidase

S-Citalopram

R-Citalopram

Adolescent Escitalopram ResponsePharmacogenomic Predictors

Strawn et al. Unpublished data.

Normal metabolizers, n=10Intermediate metabolizers, n=10

Adolescent Escitalopram ResponseLevels in Adolescent GAD


Non-adherent with treatment secondary to side effects


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Adolescent Escitalopram ResponsePharmacogenomic Predictors


Normal metabolizers, n=10Intermediate metabolizers, n=10

5‐HT Transporter GeneSLC6A4 or 5HTT or SERT

• Encoded by the SLC6A4 gene

• Responsible for the reuptake of 5-HT into the presynaptic neuron

• SSRIs inhibit this process, resulting in increased 5-HT being present at the synaptic junction

α2

SSRI

SSRI

5‐HT Transporter GeneSLC6A4 or 5HTT or SERT

• Meta-analyses of the association between 5-HTTTR polymorphism and SSRI efficacy for adult MDD (15 studies, N=1435) (Horstmann et al, 2009)– s/s variant lower remission rates (p<0.0001)– s/s and s/l variants had lower response rates

SSRI

α2

SSRI

s/s l/ls/l

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers


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Predicting Time to Response inPediatric Anxiety

How long should an SSRI trial last?

CAMS: Probability of Response in Pediatric Anxiety Disorders

If no improvement by wk 8 with sertraline, 3:1 odds against additional improvement

Strawn et al. Placebo response in pediatric anxiety disorders: results from the Child/Adolescent Anxiety Multimodal Study (CAMS). Journal of Child and Adolescent Psychopharmacology. 2017;27(6):501-508.

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Predicting Response in Pediatric Anxiety

Not all antidepressants are the same


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Meta-Analysis: Antidepressant Efficacy

Effect Size=0.62, p=0.002Weighted d proportional to 5-HT selectivity, p=0.02

Strawn et al. Depression & Anxiety. 2015 | Locher, et al. JAMA Psychiatry. 2017Wang et al. JAMA Pediatrics. 2017 | Dobson et al. J Clin Psychiatry 2019 (in press)

SSRI Effect Size: 0.65SNRI Effect Size: 0.45

SSRI Effect Size: 0.71SNRI Effect Size: 0.41

SSR

ISN

RI

Serotonergic Selectivity

R² = 0.7621

0

0.25

0.5

0.75

1

1.25

1.5

1.75

0 500 1000 1500

fluvoxamine

duloxetine

venlafaxine

sertraline

Ki NE/Ki 5-HT (Serotonergic Specificity)

Effe

ct S

ize

fluoxetineparoxetine

P = 0.010

Strawn et al. Depression & Anxiety. 2015;32(3):149-57

Network Meta-Analysis: Medication EfficacySSRIs, SNRIs and alpha-2 agonists are more effective than placebo in producing ‘treatment response’

Dobson ET, Bloch M, Strawn JR. Network meta-analysis: efficacy and tolerability of pharmacotherapy for pediatric anxiety disorders. Journal of Clinical Psychiatry. 2019;80(1):17r12064.

Network Meta-Analysis: Medication Efficacy



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Antidepressant Response in Pediatric Anxiety Disorders

SSNRI

SSRIHigh dose

SSRI

Low dose SSRI

Strawn JR, Mills JA, Sauley B, Welge JA. The impact of antidepressant dose and class on treatment response in pediatric anxiety disorders: a meta-analysis. Journal of the American Academy of Child & Adolescent Psychiatry. 2018;57(4):235–244.

SSRIs produce faster and greater improvement in anxiety symptoms

Antidepressant Dose and Response

Wehry AM, Dulemba SE, Ramsey L, Strawn JR. Pharmacogenomic Testing in Child & Adolescent Psychiatry: an Evidence-Based Review. Current Problems in Pediatrics and Adolescent Health Care 2018

Predicting Placebo Response in Pediatric Anxiety

Expectation is Critical

CAMS: Placebo Response and its Relevance for Clinicians

• Change in PARS score over the course of 12 weeks of treatment was best predicted by:– Separation anxiety disorder

(strongest predictor)– parent expectations for

treatment success– child expectations for treatment

success

Strawn JR, Dobson ET, Mills JA, Cornwall GJ, et al. Placebo Response in Pediatric Anxiety Disorders: Results from the Child/Adolescent Anxiety Multimodal Study. J Child Adolesc Psychopharmacol. 2017


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Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Meta-Analysis: SSRI and SNRI Adverse Events in Pediatric Patients

Mills and Strawn, 2019, under review

Predicting Antidepressant Side Effects in Anxiety

Activation

Activation

Activation

Impulsivity

Insomnia

Restlessness

Hyperactivity

Irritability

Disinhibition

Luft MJ, Lamy M, DelBello MP, McNamara RK, Strawn JR. Antidepressant-induced activation in children and adolescents: risk, recognition and management. Current Problems in Pediatrics and Adolescent Health Care. 2018;48(2):50-62.


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Activation and Drug Level• Antidepressant-related activation emerges

early in treatment or following an increase in dose (Reinblatt et al. 2009).

• Symptoms resolve when the dose is decreased or medication is discontinued (Riddle et al. 1990; Wilens et al. 2003).– Consistent with one prospective study of

fluvoxamine in which higher plasma fluvoxamine concentrations were associated with a greater likelihood of activation in anxious youth (Reinblatt et al, 2009, right).

• The rate of symptom resolution is related to the rate of activation symptom onset (Wilenset al. 2003).

Activation

No Activation

Luft et al. Antidepressant-induced activation in children and adolescents: risk, recognition and management. Current Problems in Pediatrics and Adolescent Health Care. 2018.

Antidepressants and Activation in Youth with Anxiety Disorders

Reinblatt et al. J Child Adolesc Psychopharmacol. 2009;19(2):119–126.

Fluvoxam

ine level

(ng/mL)

No activation

Activation

0 200

4

00 600

800

Activation and Antidepressant Class in Anxious Children & Adolescents

• SSRIs are more likely to produce activation compared to placebo.• SNRIs do not differ from placebo in terms of the likelihood of producing

activation.

Mills and Strawn, in preparation.

Prob

ability SSRI SNRIs

placebo placebo

p=0.001 p=0.074

Activation and Antidepressant Class in Anxious Children & Adolescents

• SSRIs are more likely to produce activation than SNRIs (p<0.0001)– Odds against H0: 17:1

Mills and Strawn, in preparation.

SSRI

SNRI

Activation Rate

p=0.0001

Prob

ability

Prob

ability


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Escitalopram-Related ActivationANOVA for trend p=0.029

Aldrich et al. Influence of CYP2C19 metabolizer status on escitalopram/citalopram tolerability and response in youth with anxiety and depressive disorders. Frontiers in Pharmacology 2019 (in press).

Clinical Recommendations for Managing Activation

• Rule out general medical condition • Evaluate potential contributors

– Diagnosis/Comorbidity• ADHD, manic symptoms?

– Family factors that perpetuate anxiety (e.g., accommodation)

– occult substance use, – medication adherence,

• Decrease in dose of SSRI• Consider change to another SSRI or SNRI• Consider individual or family psychotherapy• May consider short-term adjunctive benzodiazepines for

activation

Luft et al. Antidepressant-Induced Activation in Children and Adolescents: Risk, Recognition and Management. Current Problems in Pediatrics and Adolescent Health Care. 2017

Predicting Antidepressant Side EffectsWeight Gain

Antidepressant-Related Side EffectsWeight Gain and SSRIs

Calarge et al. Body composition in adolescents during treatment with selective serotonin Reuptake Inhibitors. Pediatrics 2017;140(1) :e20163943

0

0.05

0.1

0.15

0.2

0.25

0.3

BMI z-score fat mass index z-score lean body mass index z-score

CitalopramFluoxetineSertraline

p<0.0005

p<0.05p=0.05

p<0.0005 p<0.0005


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Escitalopram-Related Weight Gain

Ramsey et al. Racial differences in escitalopram/citalopram-related weight gain in children and adolescents: a natural language processing-based electronic medical record study. J Child & Adolescent Psychopharmacology. 2019 (in press)

Log-rank test for trend p=0.018

Aldrich et al. Influence of CYP2C19 metabolizer status on escitalopram/citalopram tolerability and response in youth with anxiety and depressive disorders. Frontiers in Pharmacology 2019(10):99.

Escitalopram-Related Weight Gain

Predicting Treatment-Emergent Suicidality and Self Harm in

Antidepressant-Treated Youth Dose and Medication

Antidepressants & Self-Harm• \\

Miller M, Swanson SA, Azrael D, Pate V, Sturmer T. Antidepressant Dose, Age, and the Risk of Deliberate Self-harm. JAMA Internal Medicine 2014 174(6):899-909

Modal doses:citalopram 20 mg/daysertraline 50 mg/dayfluoxetine 20 mg/day


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Antidepressants & Suicidality in Pediatric Anxiety Disorders

• \\


Treatment-emergent suicidality was significantly greater in paroxetine-treated patients compared to those receiving sertraline (logOR: 43.5, 95% CrI: [10.1 to 96.0]), placebo (logOR: 19.5, 95% CrI: [1.7 to 60.4]), and duloxetine (logOR: 20.3, 95% CrI: [1.5 to 67.7]).

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

Psychotherapy

Biomarkers

Precision Tx

Gen Psychopharm

PGx

Time course

Comparing meds

Placebo

Side Effects

Dosing

PsychotherapyBiomarkers

Predicting Psychotherapy Response in Pediatric Anxiety

The Impact of Age and Modality


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Significant linear discontinuity in slope following onset of exposure in CBT

Peris, et al. Trajectories of Change in Youth Anxiety during CBT J Consult Clin Psychol. 2015; 83(2): 239–252.

Onset of cognitiveRestructuring

component of CBT

Onset of exposure exercises

Is exposure “the”

improves symptoms?

Is exposure “the” component of CBT that

improves symptoms?

Trajectory varies by treatment and age

Peris, et al. Trajectories of Change in Youth Anxiety during CBT J Consult Clin Psychol. 2015; 83(2): 239–252.

Onset of cognitiverestructuring component

of CBT

Onset of exposure exercises

Does SSRI treatment

of CBT?

Does SSRI treatment augment the cog effect

of CBT?Are children, compared

with CBT?

Are children, compared to adolescents benefitting more from exposure when treated with CBT?

Predicting Psychotherapy Response in Pediatric Anxiety

The Impact of Comorbidity

ADHD Co-morbidity and Treatment Outcome in CAMS

• ADHD diagnosis moderated acute tx response and remission rates.

• Youth with co-occurring ADHD fared worse in the CBT condition.

– When was CBT administered?• After school

– When were stimulants more likely to have been administered?

• morning• No differences in other tx conditions.• ODD diagnosis did not moderate or predict any

treatment outcomes

Ollendick T. Treatment outcomes in anxious youth with and without comorbid ADHD in the CAMS. Anxiety & Depresive Disorders Association of America, Chicago, IL, March, 2014

CBT

ADHD

12

3

6

9


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Predicting Psychotherapy or Pharmacotherapy Response in

Pediatric AnxietyThe Impact of Severity

Anxiety Severity and Remission• Child & Adolescent

Multimodal Study– Sertraline– Sertraline + CBT– CBT– Placebo

• The most severely anxious youth probably require combined treatment (CBT+SSRI) to achieve the best outcomes.

Taylor JH et al. Monotherapy Insufficient in Severe Anxiety? Predictors and Moderators in the Child/Adolescent Anxiety Multimodal Study. Journal of Clinical Child & Adolescent Psychology. 2018. 47:2, 266-281.

02468

10121416

Severe Anxiety Moderate Anxiety

SertralineCBTSertraline+CBT

NN

T fo

r rem

issi

on

Conclusions• SSRIs/SNRIs are effective treatments for anxiety disorders

– SSRIs associated with greater and faster improvement. – Adequate trial = 6 weeks.

• Psychotherapy is effective for pediatric anxiety disorders– Comorbid conditions affect engagement and liklihood of success and require optimizing of

comorbiditiy-specific treatment. • Antidepressant side effects in adolescents

– activation may be related to drug level and metabolism. – SSRIs are associated with more activation compared to SNRIs. – Citalopram is associated with weight gain in youth with anxiety/depressive disorders

• Pharmacogenetic markers of medication metabolism suggest:– Slower metabolism may be associated with greater weight gain and activation – Extreme metabolizers (e.g., very slow and very fast) are more likely to discontinue medication– SSRI dose requires adjustment in extreme metabolizers to produce similar exposure to normal

metabolizers.

AcknowledgmentsUniversity of Cincinnati• Heidi Schroeder, BS• Melissa P. DelBello, MD, MS• Sara Varney, BS• Sarah Mossman, MA• Jeffrey Mills, PhD• Marissa Luft, BS• Eric Dobson, MD*

Duke University• Moira Rynn, MD• Scott Compton, MD

Cincinnati Children’s• Sergio Delgado, MD• Kim Cecil, PhD• Laura Ramsey, PhD• Ethan Poweleit, BS

Ann & Robert H. Lurie Children’s Hospital• John Walkup, MD

Columbia University• Amir Levine, MD

*Now MUSC

Psychopharmacologic Consultant Neuronetics X · Strawn et al. Depression & Anxiety. 2015 |Locher,...

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