Post on 24-Jan-2016
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