Pediatric Anxiety:Current and Future Approaches to

Therapeutics

Daniel S. Pine, MDDaniel S. Pine, MD

Disclosures

Sources of Research SupportSources of Research Support

National Institute of Mental HealthNational Institute of Mental Health

Paid Editorial Relationship Am J Psychiatry– Deputy Editor

Consulting Relationships None

Stock Equity (>$10,000)None

Speaker’s BureauNone

Role in pharmacology researchRole in pharmacology research

FDA Committee & Black Box VoteFDA Committee & Black Box Vote

““Off-Label” useOff-Label” use

My perspectiveMy perspective

Outline & Objectives Classifying Pediatric Anxiety & MDDClassifying Pediatric Anxiety & MDD

Broad categorization schemeBroad categorization scheme Outcome & treatment implicationsOutcome & treatment implications

Current Treatments for Pediatric AnxietyCurrent Treatments for Pediatric Anxiety

Going Beyond SSRIs & CBT?Going Beyond SSRIs & CBT? Underlying neurobiologyUnderlying neurobiology Other treatments?Other treatments?

OCDAssociations with tics, ADHD

Basal ganglia dysfunction, PANDAS Leckman, Peterson, Rosenberg, Swedo, others

PTSDLongitudinal associations with wide array of disorders

HPA axis dysfunctionDeBellis, Heim, Nemeroff, Pynoos, others

Social Anxiety, GAD, Separation Anxiety, [Phobias]

Considered as a group in most major treatment studiesBiederman, Kendal, Kessler, Pine, Rosenbaum, Weissman, others

Specific Association with MDD?Particularly GAD

Categorizing Childhood Anxiety

Longitudinal Data

Clinic-basedClinic-based

Family-basedFamily-based

Community-basedCommunity-based

Sub-clinical PrecursorsSub-clinical Precursors

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?Disorder as Adults?

Disorder asDisorder as

Adolescents?Adolescents?NoNo YesYes

NoNo 390390 3636 426426

YesYes 191191 6262 253253

581581 9898 679679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?Disorder as Adults?

Disorder asDisorder as

Adolescents?Adolescents?NoNo YesYes

NoNo 390390 3636 426426

YesYes 191191 6262 253253

581581 9898 679679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?Disorder as Adults?

Disorder asDisorder as

Adolescents?Adolescents?NoNo YesYes

NoNo 390390 3636 426426

YesYes 191191 6262 253253

581581 9898 679679

Pine et al. 1998, 2001, 2002

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?Disorder as Adults?

Disorder asDisorder as

Adolescents?Adolescents?NoNo YesYes

NoNo 390390 3636 426426

YesYes 191191 6262 253253

581581 9898 679679

Pine et al. 1998, 2001, 2002

Length of Treatment (Pine 2002)

Chronic anxiety not inevitableChronic anxiety not inevitable Stable children without symptoms need a Stable children without symptoms need a

trial off of an SSRItrial off of an SSRI Applies more to anxiety than MDDApplies more to anxiety than MDD Questions on safety, when and who to treatQuestions on safety, when and who to treat

Treatment of Pediatric Anxiety

SSRIs & BeyondSSRIs & Beyond

Specific Agents

SSRIs/SSNRIsSSRIs/SSNRIs

BenzodiazepinesBenzodiazepines

TCAsTCAs

PsychostimulantsPsychostimulants

SNRIsSNRIs

Antipsychotics (?)Antipsychotics (?)

Anticonvulsants (?)Anticonvulsants (?)

Specific Agents

SSRIsSSRIs/SSNRIs/SSNRIs

BenzodiazepinesBenzodiazepines

TCAsTCAs

PsychostimulantsPsychostimulants

SNRIsSNRIs

Antipsychotics (?)Antipsychotics (?)

Anticonvulsants (?)Anticonvulsants (?)

SSRIs & Efficacy in Pediatric Populations

SAD/GAD/Soph

OCD

MDD

SSRIs and Pediatric Anxiety: Efficacy

Evidence for efficacy in GAD, social anxiety, Evidence for efficacy in GAD, social anxiety, separation anxiety disorderseparation anxiety disorder

Particularly good evidence for fluvoxamine, Particularly good evidence for fluvoxamine, fluoxetine, paroxetine, sertraline fluoxetine, paroxetine, sertraline

CBTCBT

Rates of Improvement

StudyStudy DifferenceDifference PBOPBO SSRISSRI

RUPP Anxiety Study (2001)RUPP Anxiety Study (2001) 47%47% 29%29% 76%76%

Birmaher et al. (2003)Birmaher et al. (2003) 25%25% 36%36% 61%61%

Rynn et al. (2001)Rynn et al. (2001) 80%80% 10%10% 90%90%

Wagner et al. (2004)Wagner et al. (2004) 40%40% 38%38% 78%78%

Rynn et al. (2006)Rynn et al. (2006) 12%12% 24%24% 36%36%

TotalTotal 30%30% 31%31% 61%61%

Meta-Analysis: Rates of Improvement

NNT=3.3

Walkup J et al. N Engl J Med 2008;10.1056/NEJMoa0804633

The CAMS Study

SSRIs and Pediatric OCD

Five SSRIs have been shown to workFive SSRIs have been shown to work No robust differences among the fiveNo robust differences among the five FDA approval:FDA approval:

Prozac, Luvox, ZoloftProzac, Luvox, Zoloft CBT vs. SSRICBT vs. SSRI

Strong site differencesStrong site differences Benefit for combination?Benefit for combination? Data in adultsData in adults

Copyright restrictions may apply.

The Pediatric OCD Treatment Study (POTS) Team, JAMA 2004;292:1969-1976.

Weekly Adjusted Intent-to-Treat CY-BOCS Score, by Treatment Group

SSRIs and Controversy

SSRIs and Controversy

Biased reporting of data for efficacyBiased reporting of data for efficacy

Biased Reporting in Adult Antidepressant TrialsTurner et al. NEJM 2008

0

0 .0 50 .1

0 .1 50 .2

0 .2 50 .3

0 .3 50 .4

0 .4 5

E ffe c t S ize (H e d g e 's g )

A ll D a ta

P u b lish e d D a taO n lyU n p u b lish e dD a ta O n ly

Bias in Publication Bias in Magnitude of Clinical Effect

SSRIs and Controversy

Concerns about suicidal ideationConcerns about suicidal ideation

FDA Analysis from December, 2006

Antidepressants and Thoughts About Suicide

SSRIs and Controversy

FDA & Black BoxFDA & Black Box

Bottom Line of the SSRIs SSRIs are very effective in the treatment of SSRIs are very effective in the treatment of

pediatric anxiety.pediatric anxiety. Of the SSRIs, only fluoxetine has been Of the SSRIs, only fluoxetine has been

clearly shown to be effective in pediatric clearly shown to be effective in pediatric MDD. MDD.

Increased risk of suicidality with SSRI Increased risk of suicidality with SSRI treatment is real, but the magnitude of the treatment is real, but the magnitude of the effect is small.effect is small.

Mechanism of beneficial and adverse SSRI Mechanism of beneficial and adverse SSRI effects in a developmental contexteffects in a developmental context Studies in animal models Studies in animal models

Novel treatment approachesNovel treatment approaches The perspective of neuroscienceThe perspective of neuroscience

Attention RetrainingAttention RetrainingExtinctionExtinction

Future Directions

Mechanism of beneficial and adverse SSRI Mechanism of beneficial and adverse SSRI effects in a developmental contexteffects in a developmental context Studies in animal models Studies in animal models

Novel treatment approachesNovel treatment approaches The perspective of neuroscienceThe perspective of neuroscience

Attention RetrainingAttention RetrainingExtinctionExtinction

Future Directions

                                                                          

                Development, Anxiety, & 5-HT1a RGross et al. Nature 2002

5-HT1a receptor must be present pre-adolescence to “rescue” anxious

phenotype.

The effect of SSRIs on developing nervous system is not fully understood

Ansorge et al (2004)Science

Mechanism of beneficial and adverse SSRI Mechanism of beneficial and adverse SSRI effects in a developmental contexteffects in a developmental context Studies in animal models Studies in animal models

Novel treatment approachesNovel treatment approaches The perspective of neuroscienceThe perspective of neuroscience

Attention RetrainingAttention RetrainingExtinctionExtinction

Future Directions

VISUALVISUALCORTEXCORTEX

AMYGDALAAMYGDALA

HEART RATE

BLOOD PRESSUREBLOOD PRESSURE MUSCLEMUSCLE

VISUAL THALAMUS

LeDoux. LeDoux. Sci AmSci Am. 1994;270:50.. 1994;270:50.

Visual probe task with emotional faces

14 ms

*

17-1250 ms

Vigilance for threat = Faster RTs to probes replacing threat vs. neutral faces

Bar-Haim et al. (2007)

Mogg & Bradley

+

500 ms

AMYGDALAAMYGDALA

The circuitry of attention bias in pediatric GAD

Attention, PFC-Amygdala-Circuitry, and Pediatric Anxiety

Prolonged Threat: PFC regulates anxiety

Monk et al. 2006, 2008

Brief Subliminal Threat: Amygdala instantiates anxiety

Attention Retraining Therapy

0

2

4

6

8

10

12

Train to Neutral Train to AngryA

nxi

ety

Sco

re

Eldara, Ricona, & Bar-Haim in pressTraining of Attention

Altered Response to Stress

Any Adolescent Anxiety Disorder & Any Adult Mood/Anxiety Disorder

Disorder as Adults?Disorder as Adults?

Disorder asDisorder as

Adolescents?Adolescents?NoNo YesYes

NoNo 390390 3636 426426

YesYes 191191 6262 253253

581581 9898 679679

Pine et al. 1998, 2001, 2002

Ressler & Davis 2003

Ressler & Davis 2003

Ressler & Davis 2003

Extinction: Not forgetting but new learning

Anxiety disorders as problems in new learning

Ressler & Davis 2003

Ressler & Davis 2003

NMDA manipulation

Ressler & Davis 2003NMDA manipulations?

Copyright restrictions may apply.

Ressler, K. J. et al. Arch Gen Psychiatry 2004;61:1136-1144.

Acrophobia within the virtual environment is improved with D-cycloserine

Conclusions

Classifying Anxiety & MDDClassifying Anxiety & MDD

Efficacy of SSRIs, other agentsEfficacy of SSRIs, other agents

Going beyond SSRIsGoing beyond SSRIs