Pediatric anxiety disorders: from neuroscience to evidence ... · UPDATE ARTICLE Pediatric anxiety disorders: from neuroscience to evidence-based clinical practice Giovanni Abraha˜o

UPDATE ARTICLE

Pediatric anxiety disorders: from neuroscience toevidence-based clinical practiceGiovanni Abrahao Salum,1,2,3 Diogo Araujo DeSousa,1 Maria Conceicao do Rosario,3,4

Daniel Samuel Pine,5 Gisele Gus Manfro1,2,3

1Anxiety Disorders Outpatient Program for Child and Adolescent Psychiatry, Hospital de Clınicas de Porto Alegre (HCPA), Universidade

Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 2Graduate Program in Medical Sciences: Psychiatry, UFRGS, Porto Alegre,

RS, Brazil. 3National Science and Technology Institute for Developmental Psychiatry for Children and Adolescents (INCT), Conselho Nacional

de Desenvolvimento Cientıfico e Tecnologico (CNPq). 4Child and Adolescent Psychiatry Unit, Department of Psychiatry, Universidade Federal

de Sao Paulo (UNIFESP), Sao Paulo, SP, Brazil. 5National Institutes of Mental Health (NIMH), Intramural Research Program, Emotion and

Development Branch.

The objective of this narrative review of the literature is to describe the epidemiology, etiology,pathophysiology, diagnosis, and treatment of pediatric anxiety disorders. We aim to guide clinicians inunderstanding the biology of anxiety disorders and to provide general guidelines for the properdiagnoses and treatment of these conditions early in life. Anxiety disorders are prevalent, associatedwith a number of negative life outcomes, and currently under-recognized and under-treated. Theetiology involves both genes and environmental influences modifying the neural substrate in acomplex interplay. Research on pathophysiology is still in its infancy, but some brain regions, such asthe amygdala and the prefrontal cortex, have been implicated in fear and anxiety. Current practice isto establish diagnosis based purely on clinical features, derived from clinical interviews with the child,parents, and teachers. Treatment is effective using medication, cognitive behavioral therapy, or acombination of both. An introduction to the neuroscience behind anxiety disorders combined with anevidence-based approach may help clinicians to understand these disorders and treat them properlyin childhood.

Keywords: Child; adolescent; anxiety disorders; obsessive-compulsive disorder

Introduction

Pediatric anxiety disorders refer to a collection ofsyndromes characterized by dysfunctional fear and/oranxiety affecting children and adolescents. Fear can bedefined as a negative emotional state triggered by thepresence of a stimulus that has the potential to causeimmediate harm, while anxiety can be defined as anemotional state in which the threat is not immediatelypresent but is anticipated. Both of these emotions areadaptive and essential for survival. They are accompa-nied by cognitive representations, physical symptoms,and behavioral modifications that prepare the individual todeal with danger (fear response). Fear and anxiety areconsidered dysfunctional when intensity, duration, and/orfrequency are not proportional to the eliciting threat, andthereby cause interference, disabilities, impairment, and/or distress that are judged clinically excessive.

Anxiety disorders in childhood and adolescence areassociated with a variety of negative outcomes, includinglower educational achievement and failure to attenduniversity.1 They affect children’s functioning with peers,

school personnel, and family,2,3 are associated withgeneral psychosocial impairment and disabilities2,3 aswell as with childhood suicide risk even when they arepresent in subthreshold levels.4 Pediatric anxiety dis-orders can also persist and continue to create inter-ference as the child matures into early adulthood,especially when associated with depression.5 Later inlife, anxiety disorders are associated with poorer qualityof life,6 suicide,7 and increased mortality due to cardio-vascular diasease,8 generating a high societal burdenand costs.9 Despite high prevalence and associationswith various negative outcomes, childhood anxiety israrely recognized by parents and children as a medicalproblem, leading a minority of affected individuals toreceive the care they need.10,11 Furthermore, physicianscan fail to recognize pediatric anxiety in children who dopresent for care, and even when anxiety is recognized, itis frequently treated sub-optimally.9,12,13

The objective of this review was to describe theepidemiology, etiology, pathophysiology, diagnosis, andtreatment of pediatric anxiety disorders. Given the factthat anxiety disorders more often co-occur and given theamount of similarities among these syndromes, this paperbroadly discusses ideas that are relevant to anxietydisorders as a group.14 Moreover, when consideringindividual conditions, the review focuses in depth on fourspecific disorders: separation anxiety (SeAD), social

Correspondence: Giovanni Abrahao Salum, Hospital de Clınicas dePorto Alegre, Rua Ramiro Barcelos, 2350/2202, CEP 90035-003,Porto Alegre, RS, Brazil.E-mail: [email protected]

Revista Brasileira de Psiquiatria. 2013;35:S3–S21� 2013 Associacao Brasileira de Psiquiatria

doi:10.1590/1516-4446-2013-S108

http://dx.doi.org/10.1590/1516-4446-2013-S108

anxiety (SoAD), generalized anxiety (GAD), and panic(PD) disorders. Evidence related to specific phobias(SPs), obsessive-compulsive (OCD), and posttraumaticstress (PTSD) disorders, when relevant, is also incorpo-rated though in less detail.

Epidemiology

Prevalence

Anxiety disorders as a group constitute the most commonmental health problem in childhood and adolescence,15

affecting from 2.5 to 30% of youths.15-18 Large variationsin prevalence rates are observed among studies. Whilethe exact reasons for such variations remain unclear,most experts attribute them to methodological factorssuch as cross-study differences in the age of subjects,assessment instruments, information source, diagnosticsystem used, or variations in the application of thediagnostic criteria.19-22 Nevertheless, cross-cultural varia-bility in prevalence rates for anxiety is also likely to occur,given large differences in risk factor profiles and culturalbeliefs.20,21,23 One reasonable estimate for the globalprevalence of any anxiety disorder in the age range of 3to 17 years, adjusted for differences in methodologicalfactors, is 7.2%.24 There is no nationally representativestudy for pediatric anxiety in Brazil. The available studiesare limited to cities in the South and Southeast, wherereported prevalence is approximately 5%.25,26

Prevalence for each anxiety disorder is heavilydependent on the age range of the sample and on theage of onset patterns of each disorder. SeAD and SPhave the earliest age of onset, with half of the casesemerging before ages 5 and 8, respectively. SoAD andOCD typically emerge at early adolescence, with half ofthe cases emerging before ages 12 and 14, respectively.GAD is also common in early adolescence and less wellstudied than the other disorders, due to changes indiagnostic criteria over time. Nevertheless, current dataplace the median age of onset in late adolescence, by theages of 16-18 years. Agoraphobia, PD and PTSD are lowprevalence conditions in childhood, with higher preva-lence rates in late adolescence and early adults (medianage of onset 17, 19 and 22, respectively).15 Beyond dataon age trends, anxiety disorders have also been linked toother demographic factors. Gender is probably the mostfrequent demographic correlate of pediatric anxiety. Thefemale/male gender ratio for almost all anxiety disorder is2:1 to 3:1.27 Most studies have shown an associationbetween anxiety and lower instruction levels and worsesocioeconomic status19 but no association has beenfound with urbanization or ethnicity.16,19 Table 1 depictsthe prevalence found in two Brazilian studies and othertwo representative samples in the United States andEurope.

Natural course

Prospective studies have shown that 60-80% of adultswith full criteria for anxiety disorders report signs ofearlier, pediatric anxiety.29 Despite the fact that most

affected adults have signs of anxiety as children, inchildren followed prospectively, anxiety disorders havevariable natural course. This course typically involves oneof four trajectories: 1) spontaneous long-term remission(e.g., childhood SeAD that totally disappears in anotherwise typically developing adolescent who maturesto become a healthy adult); 2) strict homotypic continuity(e.g., SoAD in childhood persisting into SoAD in adult-hood); 3) broad homotypic continuity (e.g., SeAD inchildhood predicting PD in adulthood); and 4) sequentialheterotypic comorbidity (e.g., SoAD in childhood predict-ing latter development of major depression in adult-hood).15,19,30,31 The latter two trajectories involve acourse that has been characterized as waxing andwaning over time,32 oscillating between threshold andsubthreshold clinical conditions (resulting in high rates ofrecurrence rather than chronicity).33

The frequency of each one of these courses is highlyvariable from one longitudinal study to another.1,5,29,32,34-42

Broadly we can say that about one-third of anxiouschildren achieve a long-term remission, another third partpersists with strict or broad anxiety continuity (frequentlyaccompanied by comorbid disorders), and about one-thirdremits from anxiety and develops a sequential heterotypiccomorbidity (mainly with major depression and substanceabuse).1,29,38,40 Among a variety of potential moderatorsof the natural history, unfavorable natural courses havebeen associated with female gender, symptom severity,duration of illness, early age of onset, severe avoidanceand associated impairment, parental history of psycho-pathology, and inhibited temperament.15,43

Etiology and pathophysiology

Mental disorders reflect individual differences in brainfunction.31,44,45 Those differences are a result of acomplex combination of factors that ultimately representthe distal effects of risk genes and/or environmentalcomponents (etiological factors). These etiological riskfactors act on neural circuits (neural substrates) duringbrain development and cause quantitative and/or quali-tative abnormalities in brain functions (pathophysiologicalprocesses). This deviation from typical trajectories ofbrain development results in emotional and behavioralmanifestations of psychiatric disorders.46

Genes and environment

Family studies have shown that anxiety disorders arefamilial,47,48 whereas twin studies demonstrated thatanxiety disorders are heritable49 and that the proportionof the phenotypic variability explained by genetic factors(heritability) for anxiety disorders ranges from 25-60%.49-52

In general, this represents modest heritability for apsychiatric condition, clearly meaningful but lower thanfor highly heritable conditions, such as attention deficithyperactivity disorder (ADHD) or autism.53 In addition, onestudy54 investigating common childhood psychiatric dis-orders found that a general set of genes might nonspeci-fically influence risk for childhood psychiatric disorders,

GA Salum et al.S4

Rev Bras Psiquiatr. 2013;35(Suppl 1)

Tab

le1

Dia

gnostic

crite

ria

for

pedia

tric

anxie

tydis

ord

ers

and

epid

em

iolo

gy

28

Pre

vale

nce

(%)

Sim

plif

ied

DS

M-I

Vdia

gnost

iccrite

ria

Child

ren

Adole

scents

Age

of

onset

Genera

lized

anxie

tydis

ord

er

(GA

D)

A-

Anxie

tyand

excess

ive

worr

y,

most

of

the

days,

about

anum

ber

of

events

for

at

least

6m

onth

s.

B-

Worr

yis

difficult

tocontr

ol.

C-

At

least

one

of

the

follo

win

g:

1)

restlessn

ess;

2)

easily

fatigued;

3)

diffic

ulty

concentr

atin

gor

min

dgoin

gbla

nk;

4)

irrita

bili

ty;

5)

musc

lete

nsi

on;

6)

sle

ep

dis

turb

ance.

TA

U:

0.4

PE

L:

1.4

NC

S:

2.2

ED

SP

:0.8

ED

SP

:19

years

Socia

lanxie

tydis

ord

er

(SoA

D)

A-

Mark

ed

and

pers

iste

nt

fear

of

socia

lor

perf

orm

ance

situatio

ns

when

exposed

tounfa

mili

ar

people

or

pote

ntia

lhum

iliation/e

mbarr

assm

ent

(must

occu

rw

ith

peers

,not

just

with

adults

).B

-E

xposure

toth

efe

are

dsocia

lsituatio

npro

vokes

anxie

ty(e

.g.,

cry

ing,

tantr

um

s,

freezin

g,

or

shrinkin

g).

D-

Socia

lor

perf

orm

ance

situations

are

avoid

ed

or

faced

with

inte

nse

anxie

tyor

dis

tress.

F-

At

least

6m

onth

s.

TA

U:

0.7

PE

L:

0.1

NC

S:

9.1

ED

SP

:3.5

ED

SP

:12.5

years

Separa

tion

anxie

tydis

ord

ers

(SeA

D)

A-

Excess

ive

anxie

tyw

hen

aw

ay

from

hom

eor

from

att

achm

ent

figure

sor

when

separa

tion

isanticip

ate

d,

with

at

least

thre

eof

the

follo

win

g:

1)

dis

tress;

2)

worr

yabout

losin

gor

harm

befa

lling

att

achm

ent

figure

s;3)

worr

yth

at

an

unto

ward

event

will

lead

tosepara

tion;

4)

relu

ctance

/refu

salto

go

toschoolor

els

ew

here

;5)

fearf

ul/r

elu

ctant

tobe

alo

ne

or

withoutatt

achm

entfigure

s;6)

relu

ctance

/refu

salt

ogo

tosle

ep

withoutan

attachm

entfigure

or

tosle

ep

aw

ay

from

hom

e;

7)

nig

htm

are

sw

ith

separa

tion;

8)

physic

alsym

pto

ms.

B-

At

least

4w

eeks.

TA

U:

1.4

PE

L:

0.7

NC

S:

7.6

ED

SP

:4.5

years

Panic

dis

ord

er

(PD

)A

-R

ecurr

ent

unexp

ecte

dpanic

att

acks

(i.e

.,in

tense

anxie

tyof

sudden

onset

and

brief

dura

tion),

with

at

least

one

of

them

follo

wed

by

at

least

1m

onth

of

at

least

one

of

the

follo

win

g:

1)

concern

about

additio

nalatt

acks;

2)

worr

yabout

the

implic

ations/c

onsequence

sof

the

attack;

3)

sig

nific

ant

change

inbehavio

rre

late

dto

the

attacks.

B-

Pre

sence

or

absence

of

agora

phobia

(diffe

rentialdia

gnosis

for

PD

with

or

without

agora

phobia

).

TA

U:

0.0

PE

L:

0.0

NC

S:

2.3

ED

SP

:1.6

ED

SP

:18.5

years

Speci

fic

phobia

s(S

P)

A-

Mark

ed

and

pers

iste

ntexcess

ive

or

unre

asonable

fear

cued

by

the

pre

sence

or

anticip

ation

ofa

specifi

cobje

ctor

situatio

n(e

.g.,

flyin

g,

heig

hts

,anim

als

,in

jection,

blo

od).

B-

Exposure

toth

ephobic

stim

ulu

spro

voke

sanxie

ty(e

.g.,

cry

ing,

tantr

um

s,

freezin

g,

or

clin

gin

g).

D-

Phobic

situ

ation(s

)is

(are

)avoid

ed

or

faced

with

inte

nse

anxie

tyor

dis

tress;

F-

At

least

6m

onth

s.

TA

U:

1.0

PE

L:

1.4

NC

S:

19.3

ED

SP

:2.3

ED

SP

:7

years

Obsessiv

e-

com

puls

ive

dis

ord

er

(OC

D)

A-

Either

obsessio

ns

(i.e

.,re

petitive

intr

usiv

e/inappro

priate

thoughts

,im

puls

es,

or

att

em

pts

toig

nore

,suppre

ss,

or

neutr

aliz

eth

em

with

oth

erth

oughts

or

actions)

or

com

puls

ions

(i.e

.,re

petitiv

ebehavio

rsor

menta

lacts

,or

accord

ing

toru

les,

and

tore

duce

dis

tress

or

pre

vent

event)

.C

-O

bsessio

ns/c

om

puls

ions

cause

mark

ed

dis

tress

and

are

tim

econsum

ing

(.1

hour

aday).

TA

U:

0.1

PE

L:

0.1

ED

SP

:0.7

ED

SP

:14.5

years

Posttra

um

atic

str

ess

dis

ord

er

(PT

SD

)

A-

Past

exp

osure

toa

traum

atic

eve

nt

respondin

gw

ithin

tense

fear,

help

lessn

ess,

horr

or,

or

dis

org

aniz

ed

or

agita

ted

behavi

or.

B-

Re-e

xperience

ofth

etr

aum

atic

eventth

rough

atle

ast

one

ofth

efo

llow

ing:1)

intr

usiv

ere

colle

ctions

ofth

eeventor

repetit

ive

pla

yof

the

traum

a;

2)

dre

am

sof

the

event

or

frig

hte

nin

gdre

am

s;

3)

feelin

gas

ifth

etr

aum

atic

event

were

recurr

ing;

4and

5)

inte

nse

psyc

holo

gic

aldis

tress

or

physio

logic

alre

activity

at

exposure

toin

tern

alor

exte

rnalcues

that

resem

ble

an

aspect

of

the

traum

atic

event.

C-

Avoid

ance

ofstim

uli

asso

cia

ted

with

the

traum

aand

num

bin

gofgenera

lresponsiv

eness,w

ith

atle

ast

thre

eofth

efo

llow

ing

(notpre

sentbefo

reth

etr

aum

a):

1)

eff

ort

sto

avoid

thoughts

,fe

elin

gs,or

convers

atio

ns

rela

ted

toth

etr

aum

a;

2)

eff

ort

sto

avoid

activ

itie

s,

pla

ces,

or

people

that

aro

use

recolle

ctions

of

the

traum

a;

3)

inabili

tyto

recall

aspects

of

the

traum

a;

4)

mark

edly

dim

inis

hed

inte

rest

or

part

icip

ation

insig

nific

ant

activitie

s;

5)

feelin

gof

deta

chm

ent

from

oth

ers

;6)

restr

icte

dra

nge

of

aff

ect;

7)

sense

of

afo

reshort

ened

futu

re.

D-

Incr

ease

daro

usa

l(n

ot

pre

sent

befo

reth

etr

aum

a),

with

at

least

two

of

the

follo

win

g:

1)

diff

iculty

falli

ng

or

stayi

ng

asl

eep;2)irrita

bili

tyor

outb

urs

tsofanger;

3)

diff

iculty

conce

ntr

atin

g;4)

hyp

erv

igila

nce;5)

exa

ggera

ted

start

lere

sponse

.E

-M

ore

than

1m

onth

.

TA

U:

0.1

PE

L:

0.1

NC

S:

5.0

ED

SP

:1.3

ED

SP

:22.5

years

Dia

gnostic

crite

ria

for

all

anxie

tydis

ord

ers

:th

efo

cus

ofth

eanxie

tysym

pto

ms

isnotconfined

tofe

atu

res

ofanoth

er

menta

ldis

ord

er.

The

anxie

tysym

pto

ms

cause

clin

ically

sig

nific

antdis

tress

or

impairm

entin

socia

l,fa

mily

,school,

or

oth

er

import

antare

as

offu

nct

ionin

g.T

he

dis

turb

ance

isnotdue

toth

eeff

ects

ofa

substa

nce,genera

lmedic

alc

onditio

n,or

anoth

er

menta

ldis

ord

er.

ED

SP

=E

arly

Develo

pm

enta

lS

tages

of

Psychopath

olo

gy

(Com

posite

-In

tern

ational-

Dia

gnostic

Inte

rvie

w-

CID

I,lif

etim

e,

ages

14-2

4);

GS

M=

Gre

at

Sm

oky

Mounta

ins

Stu

dy

(Child

and

Adole

scent

Psychia

tric

Assess

ment

-C

AP

A,

3-m

onth

pre

vale

nce

,ages

9-1

6);

NC

S=

NationalC

om

orb

idity

Surv

ey

-A

dole

scent

(CID

I,lif

etim

e,

ages

13-1

8);

PE

L=

Pelo

tas

Stu

dy

(Develo

pm

ent

and

Well-

Bein

gA

ssess

ment

-D

AW

BA

,curr

ent,

ages

11-1

2);

TA

U=

Taubate

Stu

dy

(DA

WB

A,

curr

ent,

ages

7-1

4).

Pediatric anxiety disorders S5


whereas two additional sets of genes might influence riskfor two more narrow aspects of illness, reflecting still broadrisks for internalizing and externalizing disorders, respec-tively. Environmental factors generally involve non-sharedenvironment effects; meaning factors that tend to makeindividuals within a family appear different. Such factorsinclude aspects of an individual child’s school environ-ment, the unique stressors he or she experiences, andtheir social situation. This is somewhat consistent with thegeneralist genes, specialist environment model, i.e., thatcommon psychopathology mostly share their geneticliability, but are differentiated by non-shared experiences.

Twin studies that specifically focused on pediatricanxiety also support the role of both genes andenvironment, but the role of the shared environment alsoappears to be significant with lower genetic effects.These types of studies focus more narrowly on specificpresentations of anxiety, in contrast to studies morebroadly examining varieties of psychopathology. Thesemore narrow studies are incapable of specifying whatgenes and environmental factors are particularly note-worthy for pediatric anxiety. Nevertheless, no twin studyis capable of clarifying how any set of genes andenvironments affects the brain unless the study directlyassesses brain function. It is only through effects on thebrain that genes and the environment can ultimatelyresult in emotional and behavioral abnormalities.48

Candidate gene studies search for specific loci at thegenome. While these have been criticized as beingvulnerable to type I errors, they have identified severalrisk genes for anxiety disorders55; however, consistentwith type I errors, a recent review suggested thatavailable work resulted in ‘‘not a single instance ofreplication.’’56 Genome-wide association studies (GWAS)search the entire genome for signs of association. Whenperformed properly, these are less vulnerable to type Ierrors. To date, five such GWAS have been performed onanxiety disorders,57-62 though none of these focuses onchildren. Among the five, two of them produced sig-nificant results. Otowa et al.59 found two genes thatachieved genome-wide significance (transmembraneprotein 16B and plakophilin 1), but a subsequent studyfailed to replicate these findings in PD patients.58,63 Inanother study, a variant in the retinoid-related orphanreceptor alpha gene (RORA) showed genome-widesignificance for PTSD.61 In addition to these five GWASinvestigations, other studies have investigated the excessof rare copy number variations (CNVs), which are relativelarge segments of DNA that are either deleted orduplicated. In this area, the only study on PD failed tofind genome-wide significance.64

While each of these genetic strategies has advantages,they also are relatively insensitive to many mechanisms.For example, available evidence finds signs of complexgene-environment interplay in anxiety disorders,65-69 andmost research on genetics is poorly suited for capturingsuch effects. Genes and environments shape anxiety andother behaviors through a complex interplay, as it hasbeen shown through three specific relationships: 1) gene-environment interaction (genetically influenced sensitivity

to specific environments); 2) gene-environment correla-tion (genetic influences on individual variation in people’sexposure to particular environments); 3) epigenetics(environmental moderation of the effects of genesthrough influences in gene expression).70 As under-standing of genes and the environment accrue, thecomplexity of these three sets of relationships is likelyto appear even greater. This suggests that, for anxietyand other so-called complex behaviors influenced bymultiple factors, the effects of genes are far fromdeterministic and cannot be dissociated from the effectsof the child’s environmental conditions. Figure 1 illus-trates these complex relationships.

Pathophysiological processes and neural substrate

Despite a considerable advance over the last years, littleis known about the neural underpinnings of anxietydisorders in children and adolescents. Most of the workin this area focuses on information processing functionsinvolved in emotional processing (in particular threatprocessing) and cognitive control.31,71

The state of knowledge about mental processesinvolved in pediatric anxiety is currently limited.Nevertheless, tentative conclusions about existing rela-tionships can be drawn. In particular, a set of dysfunc-tional mental processes has been linked to pediatricanxiety and associated traits, such as the early-child-hood temperament of behavioral inhibition. Thesedysfunctional processes can be classified into fivegroups of information-processing functions: 1) threat-attention interaction (a tendency for anxious children toautomatically orient their attention towards or awayfrom threats)72; 2) threat appraisal (a tendency foranxious children to classify and respond to neutral orharmless stimuli as if they are dangerous)73; 3) memoryand learning processes (a tendency for anxious indivi-duals to learn different associations among safe anddangerous stimuli, as presented in fear conditioning andextinction experiments)73-75; 4) social evaluative pro-cesses (a tendency for anxious children to becomeconcerned about peer evaluation)76; 5) increasedsensitivity to rewards (a tendency for anxiety childrento more strongly alter their behavior when trying toachieve rewards).77,78

This set of findings suggests that anxiety disordersinvolve dysfunctional processes in various emotional andcognitive processes, each of which is in turn regulated byseveral brain regions that may support anxiety disorderpathophysiology.31,71 Some of the regions include: theamygdala, several portions of the prefrontal cortex -particularly the ventrolateral and dorsomedial divisions -and dysfunctions in the basal ganglia, particularly inpatients with OCD.31,71,79,80

Parenting, life events, and modeling/learning

Several studies have linked various environmental factorsto risk for anxiety. These factors include features of thehome, such as overprotective/over-controlling parenting

GA Salum et al.S6


style,81,82 as well as features that can occur either withinor outside of the home, such as stressful life events.83,84

Nevertheless, the evidence so far is limited regarding thedirection of these associations. For example, one couldhypothesize that some parents who are themselvesalready anxious might also respond to their child’s anxietyor other signs of vulnerability with parenting practices thatmay further reinforce the child’s difficulties, such asfailure to encourage infant social responsiveness.17,85 Inother words, such environmental factors could eitherpredispose to anxiety in children or children who are atrisk for anxiety may behave in such a way that theseenvironmental factors are preferentially elicited. Kender &Baker found that stressful life events, parenting, family,environment, social support, peer interactions, andmarital quality are significantly influenced by geneticfactors with heritability estimates ranging from 0.07 to0.3968 - suggesting that associations between anxiety and

parenting or other environmental factors may be geneti-cally mediated. Other studies found that the effect ofparenting was only partially genetically mediated with animportant role of non-shared environment.86 In addition,some authors suggest that some fears may arise as aresult of modeling and vicarious learning (i.e., learningthrough observation of a parent fearful response in athreatening situation for her/him)87-89 and verbal transmis-sion of threat information about novel objects.90,91

However, more experimental studies are needed to betterunderstand these phenomena.

Research on influences of parenting in psychiatricdisorder illustrates that risk and causality in psychiatryare extremely complex phenomena.68,69,92-96 In addition,heterogeneity within anxiety disorders is an importantfactor to consider. Two individuals with similar clinicalmanifestations may have different dysfunctionalprocesses, and the same dysfunctional process may be

Figure 1 Schematic representation of the etiological and pathophysiological process related to anxiety disorders. E1, mainenvironmental effects (E); G1, main genetic effects (G); E2xG2, example of gene environment interaction (GxE; geneticsensitivity to specific environments); E4RG4, example of epigenetic regulation (Epi; environmental regulation of geneexpression); E5«G5, example of gene environment correlation (rGE; genetic influences on individual variation in people’sexposure to particular environments). Genes and environments influence the developing brain. Dysfunctional circuits in theneural substrate result in deficient information processing that ultimately affect individuals’ thoughts, emotions, and/orbehaviors. Extreme dysfunctions in such system produce functional impairment and are interpreted as anxiety disorders.



responsible for different clinical manifestations. Newinitiatives, such as the Research Domain Criteria(RDoC),97,98 are attempting to clarify the ways in whichunderlying neural substrates of mental disorders con-tribute to dimensional traits that are expressed in specificbehaviors and that cut across current operationalizationof psychopathology.

Dimensional aspects of anxiety

As noted above, fear and anxiety are adaptive responsesto potential threats. The expression of these symptomscan range from normative to pathological behavioraccording to the frequency, intensity, duration and/orinterference in functioning. Therefore, anxiety disordersmay lie at the extreme end of a continuum, rather thaninvolve symptoms that are exclusive to pathologicalconditions. As such, anxiety disorders would representa variation in degree but not in kind.99 This would imply aview of normal and pathological anxiety as falling along adimension, with diagnostic thresholds reflecting clinicaland societal burden rather than discontinuous pathophy-siological states. If this view of anxiety is correct, it wouldbe quite important to study the normal development offears and learn to recognize temperaments that areclosely related to psychopathology in infants. Two suchfactors associated with anxiety are behavioral inhibitionand anxiety sensitivity.

Normal development of fears

Because the development of fear circuitry occurs early,fear responses can be observed very early in life. Thereare changes in the context of normative fear over thecourse of development, typically from immediate andconcrete stimuli during infancy to anticipatory, abstract,and more global stimuli that characterize adolescentfears. During infancy and toddlerhood, most infantsdevelop a fear of loss and shyness to strangers thatpeaks around 8 to 12 months of age, as is expressed bywariness around unfamiliar people.100,101 These fearsare often followed by separation anxiety that peaksaround 10 to 18 months marked by distress about beingseparated from parents. For most children, those fearsdisappear around 2 to 3 years of age. Early childhood(pre-school age) is characterized by normative fearsrelated to specific threats, such as meteors, clouds,blood, end of the world, being kidnapped, fairies, loss oforientation, and dying or death of others. School age ismarked by similar fears, including those directed towardswind, darkness, water, domestic animals, insects,ghosts, death, and disease, germs, natural disasters,traumatic events, harm to self or others, school anxiety,and performance anxiety. Adolescence is characterizedby fear of negative evaluation and fear of rejection frompeers. All normative fears typically decrease with ageand are transient. In adolescence, stability begins tobecome apparent. Increases in prevalence of phobic andanxiety disorders parallel decreases in normativefears.71

Behavioral inhibition and anxiety sensitivity

Given the dimensional and developmental nature ofinternalizing psychopathology, researchers have consid-ered whether certain types of temperaments observedvery early in life predict later risk for pediatric anxiety.102

Most of this work has focused on infants who displayheightened reactions to novelty and heightened sensitiv-ity to stimulus variations. Some such infants mature tobecome toddlers who withdraw from novel or unfamiliarsocial situations. This group of toddlers is said to manifestthe temperament of behavioral inhibition. This tempera-ment places the child at risk for SoAD.103,104 A recentmeta-analysis showed that behavioral inhibition wasassociated with a seven-fold increased risk for developingSoAD. Given that 15% of infants are classified asbehaviorally inhibited and about half of them will developsocial anxiety this is one of the most consistent riskfactors for social anxiety.103 Anxiety sensitivity is anotherdimensionally distributed trait that, like behavioral inhibi-tion, has been linked to pediatric anxiety. Anxietysensitivity involves beliefs that anxious symptoms willhave harmful physical, psychological, or social conse-quences to the individual. Some studies suggest that thistrait predicts PD more specifically than other forms ofanxiety, expressed later in life.105,106 Although thesedimensional traits are often seen as risk factors, analternative conceptualization is that they represent alter-native manifestations of overt anxiety disorders, as theyare expressed in younger children.

Clinical manifestations and diagnosis

Despite the dimensional perspective of fear and anxiety,diagnostic and clinical decisions (e.g., to treat or not totreat) are categorical and require a classificatory system.According to the DSM-IV, most of the anxiety disordershave the same diagnostic criteria for children, adoles-cents or adults, with some minor variations in presenta-tion (Table 1).

Screening

Some researchers argue that screening for anxietydisorder should be universal (applied to every childirrespective of their symptoms). Despite that, from apublic health perspective, only targeted screening may bepossible, and it is not clear whether universal screeningwould be in the best interest of patients. Therefore,screening may be most helpful among children whopresent with complaints about excessive fears, extremeshyness, frequent worries or rituals - some kind ofemotional distress.

Diagnostic procedures and differential diagnosis

The diagnosis of pediatric anxiety disorder is based onclinical evaluations. First, normal fears should be differ-entiated from pathological fears. The best way of doing thisis evaluating whether fears are: 1) developmentally

GA Salum et al.S8


expected or not; 2) appear with intensity, duration, andfrequency that is higher than expected for the same age;and 3) whether the fears result in distress and impairment.

Second, pathological fears should not be betterexplained by co-occurring symptoms of another psychia-tric disorder, by a co-occurring medical disease, or due tothe influences of use/abuse of alcohol and/or otherpsychoactive substances (as well as not due to with-drawal). Therefore, it is crucial to investigate the situa-tions and context in which the anxiety symptomsmanifest.

Third, primary anxiety should be classified according tothe type of anxiety disorder. Anxiety disorders share incommon several clinical features, namely dysfunctionalcognitions, physical symptoms, and behavioral dysfunc-tions such as avoidance - one of the core symptomaticcharacteristics of all anxiety disorders. However narrowlydefined in diagnostic manuals, specific anxiety disordersalso exhibit a substantial degree of phenotypic hetero-geneity. Each anxiety disorder has a symptomaticsignature. For treatment purposes, it is useful todetermine the main anxiety disorder as the condition thatproduces the greatest distress, impairment, and inter-ference in the child’s life. Figure 2 describes the coresymptomatic features of the main pediatric anxietydisorders.

Comorbidity

Pediatric anxiety disorders and other childhood psychia-tric conditions frequently co-exist in the same patient, aphenomenon known as comorbidity. In clinically referredsamples, comorbidity is often the rule rather than theexception,108 with more than half of the patients havingmore than one anxiety disorder. In community samples,anxiety also increases the chance of having additionalpsychiatric diagnoses such as major depression (oddsratio [OR] = 8.2; 95%CI 5.8-12), ADHD (OR = 3.0; 95%CI2.1-4.3), and oppositional defiant disorder/conduct dis-order (OR = 3.1; 95%CI 2.2-4.6).109 Anxiety disordersand substance abuse and dependence in childhoodappear not to be related, but this comorbidity increasedramatically in adolescents and adults, notably in sub-jects with social anxiety.110 Therefore a search forcomorbidity is imperative when evaluating children withanxiety. This includes a specific search for symptoms ofmajor depression (including suicidal ideation), substanceabuse and dependence, ADHD, and oppositional defiantdisorder. Two other conditions that are not necessarilydisorders but are rather specific behaviors also frequentlypresent in anxious children. These conditions areselective mutism, which is the failure to speak in specificsetting despite full use of language at home, and schoolrefusal, which is the failure to attend to school.

The high degree of comorbidity between anxietydisorders, as a group, and depression is clearly notable.In terms of associations between depression and one oranother specific anxiety disorder, evidence is mixed interms of whether associations are particularly strong withspecific conditions. Some studies showed particularly

strong associations with GAD, potentially reflecting asingular higher order structure for the two conditons.111

Other findings appear less specific and more stronglyreflecting developmental variations.38

Assessment

A proper assessment of psychiatric symptoms in child-hood involves information derived from the child,parents, and teachers. Particularly for anxiety disorders,the child information is extremely valuable. Since someof the symptoms involve emotions, cognitions, andbehaviors that may not involve the parent, it is imperativeto consider the child’s report. Younger children may havedifficulties communicating their symptoms as well astheir associated distress and impairments to the physi-cian.15 In these cases, parental and teacher informationmay be more valuable, but clinicians still should bevigilant for signs of avoidance expressed by the child.The clinician should be aware that parents often look forhelp with unexplained physical complaints reflectingheightened arousal (headaches, stomachaches, nau-sea, vomiting, diarrhea, muscle tension, and difficultywith sleep) that may indicate an underlying pediatricanxiety.112

As mentioned above, the diagnosis of any anxietydisorder is clinical. Although several studies link anxietyto various biological or genetic factors, the magnitude ofthese associations is far too small to be of clinical usewhen evaluating individual children. Some structuredinterviews and/or rating scales may be helpful to: 1)screen for anxiety symptoms in non-specialized settings;2) assess symptom severity; and 3) monitor treatmentgains. Table 2 depicts a variety of clinician, self andparent rated instruments that may be useful in researchand clinical practice.

Treatment

Both medication and psychotherapy are effective in thetreatment of pediatric anxiety symptoms. Literature isreviewed below in four specific areas: 1) non-OCDanxiety disorders (SeAD, SoAD, GAD, and PD); 2)OCD; 3) PTSD; 4) SP.

Because PD is exceptionally rare in childhood andadolescence, insufficient evidence exists from controlledstudies to guide treatment.155 Therefore, clinical manage-ment of PD is often considered as an extension of thecurrently available evidence for more common and betterstudied anxiety disorders (e.g., SeAD, SoAD and GAD).SPs are also highly comorbid with other anxiety dis-orders. When isolated, treatment should use cognitivebehavioral therapy (CBT), with exposure to the fearedobject combined with cognitive techniques during theexposure (whether in vivo, imaginary, or virtual) thatfacilitate extinction. Too few studies examine efficacy ofmedication in SP to inform recommendations, probablybecause CBT, the less invasive interventions, is typicallyeffective. Evidence regarding the treatment of PTSD andother consequences of trauma in children most deeply



examines CBT, where again, evidence of efficacy isstrong.156 Because the few studies examining medicationefficacy in pediatric PTSD are generally equivocal, CBTshould be the first-line treatment in children presentingwith posttraumatic anxiety.157 Due to a more specializedcharacterization of the PTSD treatment, this topic will notbe further discussed here. Additional information can befound elsewhere.157

Medication + psychoeducation

Placebo-controlled clinical trials demonstrate efficacy forselective serotonin reuptake inhibitors (SSRIs; fluoxetine,fluvoxamine, paroxetine, and sertraline) in both pediatricOCD and non-OCD disorders.158 Some trials alsosupport the use of serotonin and norepinephrine reuptakeinhibitor (SNRI) venlafaxine for non-OCD disorders.158

Figure 2 Algorithm for the diagnostic assessment of pediatric anxiety disorders (based on Salum et al.107). ADHD = attentiondeficit hyperactivity disorder; ODD = oppositional defiant disorder

GA Salum et al.S10


Tab

le2

Instr

um

ents

for

the

assessm

ent

of

anxie

tysym

pto

ms

and

dia

gnosis

of

anxie

tydis

ord

ers

inchild

ren

and

adole

scents

Clin

icalin

str

um

ents

for

the

dia

gnosis

of

pedia

tric

anxie

ty

Instr

um

ent

Rate

r(info

rmant)

Dia

gnosis

Estim

ate

dtim

eD

iagnostic

syste

m

Psy

chom

etr

icpro

pert

ies

(for

anxie

tydis

ord

ers

sect

ion

when

availa

ble

separa

tely

)

Relia

bili

tyV

alid

ity

K-S

AD

S*

(E/P

L)1

13-1

15

Clin

icia

n(C

,P

,C

LIN

)C

urr

ent/lif

etim

e--

DS

M-I

VT

R:

0.8

0(c

urr

ent)

;0.6

0(lifetim

e)

IR:

93%

-100%

(curr

ent)

;100%

(lifetim

e);*k

=0.9

(anxie

ty)

--

DA

WB

A*

26,1

16,1

17

Lay/C

linic

ian

(C,

P,

T,

CLIN

);C

OM

P(C

,P

,T

,C

LIN

)

Curr

ent

30-5

0m

inD

SM

-IV

;IC

D-1

0IR

:*k

=0.9

1(inte

rnaliz

ing)

CO

NV

:0.1

3-0

.48

(DIS

C-I

V);

0.2

3-0

.48

(CA

PA

);dia

gnosed

cases

pro

bably

more

severe

than

DIS

C-I

Vand

CA

PA

DIS

CR

:hig

her

rate

of

dia

gnosis

ina

clin

icth

an

ina

com

munity

sam

ple

(OR

=13.3

)C

hIP

S*

118,1

19

Clin

icia

n(C

,P

,C

LIN

)C

urr

ent

20-5

0m

inD

SM

-IV

+P

sychoso

cia

lstr

essors

IR:

0.9

0-1

.00

CO

NV

:hig

hle

vels

ofagre

em

entw

ith

DIC

Aand

clin

icia

n’s

dia

gnosi

s

DIS

C-I

V116,1

20

Clin

icia

n(C

,P

,C

LIN

);C

OM

P(C

,P

,C

LIN

)C

urr

ent

70

min

DS

M-I

V;

ICD

-10

TR

:0.4

8-0

.86

CO

NV

:13-0

.48

(DA

WB

A);

0.2

1-0

.61

(CA

PA

)D

ICA

-IV

121,1

22

Clin

icia

n(C

,P

,C

LIN

);C

OM

P(C

,P

,C

LIN

)C

urr

ent

30-1

20

min

DS

M-I

V--

--

ISC

A123

Clin

icia

n(C

,P

,C

LIN

)C

urr

ent

45-9

0m

in(C

);120-1

5m

in(P

)D

SM

-IV

IR:

0.9

5--

AD

IS-C

124,1

25

Clin

icia

n(C

,P

,C

LIN

)C

urr

ent

--D

SM

-IV

(focus

on

anxie

tydis

ord

ers

)T

R:

0.8

0to

0.9

2IR

:0.8

0-1

.00

--

CA

PA

116,1

26,1

27

Clin

icia

n(C

,P

,C

LIN

)C

urr

ent

60

min

DS

M-I

V;

ICD

-10

TR

:0.7

4-0

.79

CO

NV

:0.2

3-0

.48

(DA

WB

A);

0.2

1-0

.61

(DIS

C-I

V)

PA

PA

128

Clin

icia

n(P

,C

LIN

);C

OM

P(P

,C

LIN

)C

urr

ent

100

min

DS

M-I

V;

ICD

-10

+R

DC

-PA

;D

C:

0-3

RT

R:

0.7

4--

CID

I-A

16,1

29

Lay

(C);

CO

MP

Curr

ent/lif

etim

e2.5

hours

(C)

DS

M-I

V;

ICD

-10

--C

ON

V:

Are

aU

nder

the

Curv

e.

0.7

9(K

SA

DS

-PL)

Ratin

gscale

sfo

rth

easse

ssm

ent

of

anxie

tysym

pto

ms

within

abro

ad

anxie

tyconstr

uct

Sca

leR

ate

rN

um

ber

of

item

sE

stim

ate

dtim

e

Psy

chom

etr

icpro

pert

ies

Relia

bili

tyV

alid

ityC

uto

ff

ST

AI-

C*

130,1

31

Self

20

(sta

te)

+20

(tra

it)20

min

----

--R

CM

AS*

132,1

33

Self

37

15

min

IC:

0.8

3-0

.85

*IC

:0.8

5*T

R:

0.8

8

----

BA

I-Y

134

Self

20

10

min

----

--

Rating

scale

sfo

rth

eassess

ment

of

anxie

tysym

pto

ms

of

various

anxie

tydim

ensio

ns

Sca

leR

ate

rItem

sE

stim

ate

dtim

eD

imensio

ns

of

evalu

atio

n

Psychom

etr

icpro

pert

ies

Relia

bili

tyV

alid

ityC

uto

ff

PA

RS

135,1

36

Clin

icia

n(C

,P

,C

LIN

)50

+7-ite

mseverity

scale

20-3

0m

inG

A;

SoA

;S

eA

IC:

0.6

4T

R:

0.5

5IR

:0.9

7

CO

NV

:0.6

1(C

GI-

S)

DIV

G:

0.1

8-0

.33

(CD

RS

)T

RE

AT

:8-1

0(8

4-9

4%

SE

NS

;82-9

0%

SP

EC

)

Continued

on

next

page



Tab

le2

Continued

Rating

scale

sfo

rth

eassessm

ent

of

anxie

tysym

pto

ms

of

various

anxie

tydim

ensio

ns

Sca

leR

ate

rIt

em

sE

stim

ate

dtim

eD

imensio

ns

of

evalu

atio

n

Psychom

etr

icpro

pert

ies

Relia

bili

tyV

alid

ity

Cuto

ff

SC

AR

ED*

137-1

40

Self

and

pare

nt

41

15

min

GA

;P

AN

IC-S

OM

AT

;S

eA

;S

oA

;S

CH

OO

LIC

:0.9

0*IC

:0.9

0T

R:

0.8

6*T

R:

0.8

1

*C

ON

V:

0.8

1(M

AS

C)

*D

IVG

:0.5

8(C

DI)

DIS

CR

:anxie

tydis

ord

ers

vs.

oth

er

psyc

hia

tric

dis

ord

ers

*D

ISC

R:

anxie

tydis

ord

ers

vs.

contr

ol

DX

:o

26

(71%

SE

NS

;61-7

1%

SP

EC

)*D

X:o

23

(81.8

%S

EN

S;

52.0

%S

PE

C)

SC

AS*

141-1

43

Self

and

pare

nt

38

15

min

GA

;P

AN

IC-A

G;

SeA

;S

oA

;O

C;

FE

AR

S

IC:

0.9

2T

R:

0.6

0C

ON

V:

0.7

1(R

CM

AS

)D

IVG

:0.4

8(C

DI)

DIS

CR

:anxie

tydis

ord

ers

vs.

contr

ol

DX

:o

40

boys

ages

8-

11;o

33

boys

ages

12-

15;o

50

girls

ages

9-1

1;

o39

girls

ages

12-1

5M

AS

C144

Self

and

pare

nt

39

15

min

SO

MA

T;

HA

;S

eA

;S

oA

IC:

0.9

0T

R:

0.7

9-0

.93

CO

NV

:0.6

3(R

CM

AS

)D

IVG

:0.1

9(C

DI)

--

Rating

scale

sfo

rth

eassess

ment

of

anxie

tysym

pto

ms

of

aspecifi

canxie

tydim

ensio

n

Sca

leR

ate

rIt

em

sE

stim

ate

dtim

eD

imensio

nof

evalu

atio

n

Psychom

etr

icpro

pert

ies

Relia

bili

tyV

alid

ity

Cuto

ff

LS

AS

-CA

145

Clin

icia

n(C

,P

,C

LIN

)24

--S

oA

IC:

0.9

5-0

.97

TR

with

IR:

0.9

4C

ON

V:

0.7

5(S

PA

I-C

)D

IVG

:0.3

8(C

DR

S-R

)D

ISC

R:

soci

alphobia

vs.

oth

er

anxie

tydis

ord

ers

and

contr

ol

DX

:o

23

socia

lphobia

vs.

contr

ol(9

5.9

%S

EN

S;

100%

SP

EC

);o

30

socia

lphobia

vs.

oth

er

anxie

tydis

ord

ers

(91.8

%S

EN

S;

65.2

%S

PE

C)

SP

AI-

C*

146-1

49

Self

26

--S

oA

IC:

0.9

5/*0.9

4T

R:0.6

3-0

.86

/*0.7

8D

ISC

R:

socia

lphobia

vs.

contr

ol

*D

ISC

R:

soci

alphobia

vs.

contr

ol

DX

:o

19

(30%

FN

;26%

FP

)C

Y-B

OC

S150-1

52

Clin

icia

n(C

,P

,C

LIN

),self

and

pare

nt

81

+10-ite

mseve

rity

scale

--O

CIC

:0.8

7-0

.90

IR:

0.8

4T

R:

0.7

9

CO

NV

:0.6

2(L

OI-

CV

)D

IVG

:0.3

4(C

DI)

;0.3

7(C

MA

S)

TR

EA

T:

14

(91%

SE

NS

;90%

SP

EC

)

DY

BO

CS*

153

Clin

icia

n(C

,P

,C

LIN

)88

+3

item

seve

rity

for

each

OC

sym

pto

m

40

min

OC

D:

aggre

ssiv

e,

sym

metr

y,

conta

min

ation,

hoard

ing,

mis

cella

neous

IC:

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3IR

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0.9

8C

ON

V:

0.7

9(Y

BO

CS

)D

IVG

:lo

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ears

on

coeff

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nts

with

HA

M-A

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AM

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YG

TS

S

--

FS

SC

-R154

Self

80

--F

EA

RS

IC:

0.9

4-0

.95

TR

:0.5

5-0

.82

CO

NV

:0.4

6-0

.51

(ST

AI-

C)

DIS

CR

:schoolphobia

vs.

contr

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--

AD

IS-C

=A

nxie

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isord

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Inte

rvie

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chedule

for

Child

ren;A

G=

agora

phobia

;B

AI-

Y=

Beck

Anxie

tyIn

vento

ryfo

rY

outh

;C

=child

ren

as

info

rmant;

CA

PA

=C

hild

and

Adole

scentP

sychia

try

Ass

essm

ent;

CD

I=

Child

ren’s

Depre

ssio

nIn

vento

ry;

CD

RS

=C

hild

ren’s

Depre

ssio

nR

atin

gS

cale

;C

DR

S-R

=C

hild

ren’s

Depre

ssi

on

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gS

cale

,R

evis

ed;

CG

I-S

=C

linic

alG

lobal

Impre

ssio

n,

Severity

Sca

le;

ChIP

S=

Child

ren’s

Inte

rvie

wfo

rP

sychia

tric

Syndro

mes;

CID

I-A

=C

om

posite

Inte

rnationalD

iagnostic

Instr

um

ent,

Adole

scent

adapta

tion;

CLIN

=finalclin

icia

nim

pre

ssio

n;

CY

-BO

CS

=C

hild

ren

Yale

-Bro

wn

Obsessiv

e-C

om

puls

ive

Sca

le;

CO

MP

=com

pute

r-assi

ste

d;

CO

NV

=converg

ent;

DA

WB

A=

Develo

pm

ent

and

Wellb

ein

gA

ssessm

ent;

DIC

A=

Dia

gnostic

Inte

rvie

wfo

rC

hild

ren

and

Adole

scents

;D

ISC

-IV

=D

iagnostic

Inte

rvie

wS

chedule

for

Child

ren,

Fourt

hE

diti

on;

DIS

CR

=dis

crim

inant;

DIV

G=

div

erg

ent;

DX

=crite

ria

toth

edia

gnosis

of

pedia

tric

anxie

tydis

ord

ers

;D

YB

OC

S=

Dim

ensio

nalY

ale

-Bro

wn

Obsessiv

e-C

om

puls

ive

Sca

le;

FE

AR

S=

specifi

cphobia

s;F

SS

C-R

=F

ear

Surv

ey

Sch

edule

for

Child

ren,

Revis

ed;G

A=

genera

lized

anxie

ty;F

N=

fals

enegatives;F

P=

fals

epositiv

es;H

A=

harm

avoid

ance;H

AM

-A=

Ham

ilton

Anxie

tyR

ating

Scale

;H

AM

-D=

Ham

ilton

Depre

ssio

nR

ating

Scale

;IC

=in

tern

alconsis

tency;

IR=

inte

rrate

r;IS

CA

=In

terv

iew

Schedule

for

Child

ren

and

Adole

scents

;K

-SA

DS

-E=

Sch

edule

for

Aff

ective

Dis

ord

ers

and

Schiz

ophre

nia

for

Sch

ool-A

ge

Child

ren,

Epid

em

iolo

gic

Vers

ion;K

-SA

DS

-PL

=S

chedule

for

Aff

ectiv

eD

isord

ers

and

Sch

izophre

nia

for

Sch

ool-A

ge

Child

ren,P

resentand

Lifetim

eV

ers

ion;LO

I-C

V=

The

Leyto

nO

bsessio

nalI

nvento

ry,

Child

Vers

ion

Surv

ey

Form

;LS

AS

-CA

=Lie

bow

itz

Socia

lA

nxie

tyS

cale

for

Child

ren

and

Adole

scents

;M

AS

C=

Multi

dim

ensio

nalA

nxie

tyS

cale

for

Child

ren;

OC

=obsessio

ns-c

om

puls

ions;

OC

D=

obsessiv

e-c

om

puls

ive

dis

ord

er;

P=

pare

ntas

info

rmant;

PA

PA

=P

re-S

choolA

ge

Psychia

tric

Ass

essm

ent;

PA

NIC

=panic

att

acks;

PA

RS

=P

edia

tric

Anxie

tyR

ating

Sca

le;R

CM

AS

=R

evis

ed-C

hild

ren’s

Manifest

Anxie

tyS

cale

;R

DC

-PA

=R

esearc

hD

iagnostic

Crite

ria,

Pre

schoolA

ge;

SC

AR

ED

=S

cre

en

for

Child

Anxie

tyR

ela

ted

Em

otio

nalD

isord

ers

;S

CA

S=

Spence

Child

ren’s

Anxie

tyS

cale

;S

CH

OO

L=

schoolphobia

;S

eA

=separa

tion

anxie

ty;S

EN

S=

sensib

ility

;S

OM

AT

=som

atic/

physic

alsym

pto

ms;

SoA

=socia

lanxie

ty;S

PA

I-C

=S

ocia

lP

hobia

and

Anxie

tyIn

vento

ryfo

rC

hild

ren;

SP

EC

=specifi

city;

ST

AI-

C=

Sta

te-T

rait

Anxie

tyIn

vento

ryfo

rC

hild

ren;

T=

teacher

as

info

rmant;

TR

=te

st-

rete

st;

TR

EA

T=

crite

ria

tore

mis

sio

n/r

esponse

totr

eatm

ent;

Y-B

OC

S=

Yale

-Bro

wn

Obsessiv

e-C

om

puls

ive

Sca

le;

YG

TS

S=

Yale

Glo

balT

icS

everity

Sca

le.

*In

str

um

ent

with

publis

hed

refe

rence

of

transla

tion/c

ross-c

ultu

raladapta

tion

toB

razil

and

psyc

hom

etr

icpro

pert

ies

of

the

Bra

zili

an

vers

ion;

--In

form

ation

not

availa

ble

or

restr

icte

dto

the

instr

um

ent’s

manual.

GA Salum et al.S12


Regarding tricyclic antidepressants (TADs), one placebo-controlled study supported the effectiveness of clomipra-mine in the treatment of OCD,159 as did two studies inchildren with school refusal.30 The magnitude of medica-tion response can be quantified using various metrics.The so-called number-needed-to-treat (NNT) is emergingas a current standard. With this metric, estimates are thatapproximately four patients should be using the afore-mentioned drugs in the anxiety disorders treatment inorder to one to achieve clinical response rates (n=14studies/2,102 patients; medication 58.1% vs. placebo31.5%; RR = 1.9; NNT = 4).158 This represents a verystrong, robust clinical effect, relative to other conditions.For example, the NNT in either pediatric or adultdepression for most medication treatments is not half aspotent. There is evidence of the decrease in all anxietysymptoms with these medications. There is no directevidence that any of these medications offer betterresponses to treatment or are better tolerated.158

However, a mixed comparison meta-analysis found thatbetween SSRIs and venlafaxine, venlafaxine was lessefficacious than fluvoxamine and paroxetine and lesstolerated than fluvoxamine, paroxetine, and sertraline.160

Besides the SSRIs and venlafaxine, three studiesabout the use of imipramine among patients with anxietydisorders have demonstrated its effectiveness in non-OCD disorders.161 However, TADs are consideredsecondary choices due to their less favorable adverseeffects and the fact that they require continuous monitor-ing of blood and cardiac irregularities.158 There is noevidence supporting the use of benzodiazepines in thetreatment of pediatric anxiety disorders.162

It is vital to emphasize that psychoeducation is anessential part of the treatment of anxiety disorders.Psychoeducation includes the explanation of the char-acteristics of the symptoms, course, treatment strategies,potential side effects, duration of treatment, etc.Moreover, it is critical to verify that the patient is usingthe medication adequately. More frequent visits in thebeginning of the treatment (weekly, fortnightly) or aphone-based follow-up are good alternatives to ensureand increase treatment compliance. An algorithm tochoose among the therapeutic options is depicted inFigure 3. The most used first-line medications in thetreatment of anxiety disorders, their usage, and adverseeffects are shown in Table 3.

Psychotherapy

CBT is the approach with stronger evidence of effective-ness as compared to waiting lists or attention controlinterventions for both OCD163-165 and non-OCD pediatricanxiety disorders.164-166 The overall effect size of CBT forpediatric anxiety in a meta-analysis involving 48 studies(n=3,740) was 0.66 (compared to passive control 0.77and to active control 0.39; both significant), demonstrat-ing a key role of non-specific factors.164 The effect sizefor non-CBT interventions was not significant.164

Treatment target CBT (specific to one anxiety disorder)and individual treatments (as opposed to groups) had a

larger effect size than treatment targeting several anxietydisorders and group CBT.164 Clinical trials have alsoshown that CBT may have better results for treating OCDwhen family members are involved to reduce the levels offamily accommodation (the different ways that familymembers may respond to the patient’s symptoms byfacilitating avoidance, assisting on ritualistic behaviors, orinadvertently participating in rituals).167

Combined treatment

Two large studies have evaluated the combined treatmentas compared to the monotherapy and placebo compo-nents.108,168 For non-OCD anxiety disorders, theCBT+sertraline combined treatment was more effectivethan both monotherapy conditions and the placebocondition.108 For OCD, the combined treatment was moreeffective than the sertraline monotherapy and the placeboconditions, but there was no difference between thecombined treatment and the CBT monotherapy.168 Datafrom this study investigating moderator factors of thesetherapy conditions have demonstrated that, for patientswith a family history of OCD, the combined treatment or thesertraline monotherapy condition are preferable.169

Conversely, for patients with comorbid OCD and ticdisorders - a frequent comorbidity -, the combinedtreatment or the CBT are preferable.170 Moreover, inthese cases, the combination of SSRI and alpha-adrener-gic agonists or anti-psychotics might be an option.171

Other treatments and future perspectives

Innovative treatments for anxiety disorders have beendeveloped from the neuroscience field, such as the d-cycloserine combined with behavioral techniques172 andthe attentional bias modification treatment.173,174

Regulators of glutamatergic neurotransmission, such asriluzole175 and N-acetylcysteine,176 have also beenexamined in adolescents diagnosed with OCD.Although promising, these treatments do not yet presentlong-term outcomes and are currently restricted toresearch settings.

Studies in adults and children have demonstrated thatinterventions focusing on the individual’s lifestyle, such asphysical exercise, are associated with improvements inanxiety and depressive symptoms,177-179 and exerciseshould be encouraged. Evidence from studies with adultsamples have also stated that complementary treatmentswith kava,180 valerian,181 passiflora,182 meditation,183 orhealing touch184 have inconclusive benefits in thetreatment of anxiety disorders, with not enough evidenceto recommend their use.

Monitoring, refractoriness, referring

Due to the unfavorable natural history of anxiety disorders,it is highly important to monitor anxiety symptoms andpotential side effects objectively and systematically.185

Some studies have suggested that SSRI treatments mightlead to an increase in suicidality among children. Further



Figure 3 Algorithm for the management of pediatric anxiety disorders (based on Salum et al.107). CBT = cognitive behavioraltherapy; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder; PD = panic disorder; PTSD =posttraumatic stress disorder; SeAD = separation anxiety disorder; SoAD = social anxiety disorder; SP = specific phobias;SNRI = serotonin and norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor

GA Salum et al.S14


Tab

le3

Main

dru

gs

used

inth

etr

eatm

ent

of

pedia

tric

anxie

tydis

ord

ers

Dru

g(G

RA

DE

)

Dru

guse

recom

mendations

Child

/Adole

sc

,12

years

OR

Adole

sco

12

years

with

low

weig

ht

Dru

guse

recom

mendatio

ns

Adole

sc

with

norm

alw

eig

ht

OR

Child

ren

with

OC

DM

ain

chara

cte

ristics

(advanta

ges/

dis

adva

nta

ges)

SS

RI

Indic

ations:

non-O

CD

anxie

tydis

ord

ers

(GA

D,

SoA

D,

SeA

D)

+P

Dand

OC

DC

ontr

a-indic

ations:

MA

OI

use,

pim

ozid

euse,

hypers

ensi

tivity

toth

edru

gM

ost

com

mon

advers

eeff

ects

of

the

cla

ss:

nause

a,headache,dro

wsin

ess,in

som

nia

,diz

zin

ess,decre

ased

appetite

,abdom

inalpain

,nerv

ousness,exce

ssiv

esw

eatin

g,

dry

mouth

,tr

em

or,

decre

ased

sexu

aldesire,

dela

yed

eja

cula

tion,

anorg

asm

ia,

restle

ssness,

asth

enia

,abnorm

alpla

tele

taggre

gation,

and

ble

edin

g.

Flu

oxetine

(B)

Pill

s:

10

and

20

mg

Ora

lsolu

tion:

20

mg/m

L

Reco

mm

endatio

n:

start

with

asi

ngle

dose

of

5m

g/d

ay

inth

em

orn

ing

mealfo

r1

week,

incr

ease

to10

mg/d

ay

and

wait

for

thera

peutic

resp

onse

(4-6

weeks

),w

ithin

crease

sin

dose

(+5

mg/d

ay

each

week)

acc

ord

ing

tocl

inic

alre

sponse

and

tole

rance

until

the

maxi

mum

dose

of20-3

0m

g/d

ay,

acc

ord

ing

toage

and

weig

ht.

Recom

mendation:

sta

rtw

ith

asin

gle

dose

of

10

mg/d

ay

inth

em

orn

ing

mealfo

r1

week,

incre

ase

to20

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+10

mg/d

ay

each

week)

accord

ing

toclin

icalre

sponse

and

tole

rance

untilth

em

axi

mum

dose

of

40-6

0m

g/d

ay,

acco

rdin

gto

age

and

weig

ht.

-C

om

ple

xm

eta

boliz

atio

n(inhib

itsp450

CY

P2D

6and

CY

P3A

4)

-A

mong

SS

RIs

,it

isth

elo

ngest

HL

(HL

=4-6

days

;m

eta

bolit

e=

4-1

6days

)-

Am

ong

SS

RIs

,it

isth

em

ost

stim

ula

nt

-In

gestio

nw

ith

food

reduces

nausea

-A

ppro

ved

by

the

FD

Afo

rdepre

ssio

nand

OC

Din

child

ren

Flu

voxam

ine

(A)

Pill

s:

100

mg

Reco

mm

endatio

n:

start

with

asi

ngle

dose

of

25

mg/d

ay

atnig

htm

eals

(no

chew

ing),

incr

ease

to50

mg/d

ay

and

wait

for

thera

peutic

resp

onse

(4-6

weeks

),w

ithin

crease

sin

dose

(+25

mg/d

ay

each

week)

acc

ord

ing

tocl

inic

alre

sponse

and

tole

rance

until

the

maxi

mum

of200

mg/d

ay,

acc

ord

ing

toage

and

weig

ht.

Ifa

dosa

ge

hig

her

than

50

mg/d

ay

isnece

ssary

,th

edaily

dose

should

be

div

ided

intw

o(larg

er

part

at

nig

ht)

.

Recom

mendation:

sta

rtw

ith

asin

gle

dose

of

50

mg/d

ay

at

nig

ht,

incre

ase

to100

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+50

mg/d

ay

each

week)

acco

rdin

gto

clin

icalre

sponse

and

tole

rance

until

the

maxi

mum

dose

of

300

mg/d

ay,

accord

ing

toage

and

weig

ht.

Ifa

dosage

hig

her

than

100

mg/d

ay

isnecessary

,th

edaily

dose

should

be

div

ided

intw

o,

with

the

larg

er

part

at

nig

ht.

-D

rug

absorp

tion

incre

ase

sw

hen

ingeste

dw

ith

food

(but

itshould

not

be

chew

ed)

-S

hort

HL

=15

hours

(in

hig

her

dosage,it

must

be

used

intw

odaily

dose

s).

-It

pre

sents

are

lativ

epro

babili

tyof

causin

gw

ithdra

walsyndro

me

Paro

xetine

(C)

Pill

s:

10,

20,

and

30

mg

Recom

mendatio

n:

sta

rtw

ith

asin

gle

dose

of

5m

g/d

ay

inth

em

orn

ing

for

1w

eek,

incre

ase

to10

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+5

mg/d

ay

each

week)

accord

ing

toclin

icalre

sponse

and

tole

rance

untilth

em

axi

mum

dose

of

50-6

0m

g/d

ay,

acco

rdin

gto

age

and

weig

ht.

Recom

mendation:

sta

rtw

ith

asin

gle

dose

of

10

mg/d

ay

inth

em

orn

ing

for

1w

eek,

incre

ase

to20

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ase

sin

dose

(+5

mg/d

ay

each

week)

acco

rdin

gto

clin

icalre

sponse

and

tole

rance

untilth

em

axi

mum

dose

of

40-6

0m

g/d

ay,

acco

rdin

gto

age

and

weig

ht.

-C

om

ple

xm

eta

boliz

ation

(substa

ntially

inhib

itsp450

[CY

P2D

6])

-A

mong

SS

RIs

,it

isth

ele

ss

stim

ula

ntand

the

most

sedative

-A

mong

SS

RIs

,it

isth

eone

with

more

anticholin

erg

iceffects

-S

hort

HL

=21

hours

(with

dra

walsyndro

me)

Sert

ralin

e(A

)P

ills:

25,

50,

and

100

mg

Reco

mm

endatio

n:

start

with

asi

ngle

dose

of

12.5

mg/d

ay

inth

em

orn

ing

mealfo

r1-2

weeks

,in

crease

to25

mg/d

ay

and

wait

for

thera

peutic

resp

onse

(4-6

weeks

),w

ithin

crease

sin

dose

(+12.5

mg/d

ay

each

week)

acc

ord

ing

tocl

inic

al

resp

onse

and

tole

rance

until

the

maxi

mum

dose

of

200

mg/d

ay,

acc

ord

ing

toage

and

weig

ht.

Recom

mendation:

sta

rtw

ith

asin

gle

dose

of

25

mg/d

ay

inth

em

orn

ing

mealfo

r1-2

weeks,

incre

ase

to50

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+25

mg/d

ay

each

week)

accord

ing

toclin

ical

response

and

tole

rance

untilth

em

axim

um

dose

of

200

mg/d

ay,

accord

ing

toage

and

weig

ht.

-F

ew

dru

gin

tera

ctio

ns

(few

eff

ects

p450

[CY

P2D

6]a

nd

min

imum

effect

sp450

[CY

P3A

4])

-A

mong

SS

RIs

,it

isth

eone

thatm

ost

causes

nause

a-

Itcan

be

stim

ula

nt

-D

rug

absorp

tion

incre

ase

sw

hen

ingeste

dw

ith

food

-A

vera

ge

HL

=26

hours

(+m

eta

bolit

e64-1

04

hours

)

SN

RI

Indic

ations:

non-O

CD

anxie

tydis

ord

ers

(GA

D,

SoA

D,

SeA

D)

Contr

ain

dic

ations:

hypers

ensiti

vity

toM

AO

IM

ost

com

mon

advers

eeffects

:w

eig

ht

loss,

nause

a,

insom

nia

,tr

em

or,

sexualdysf

unction,

sw

eatin

g,

dry

mouth

,ble

edin

g,

hig

hblo

od

pre

ssure

.

Venla

faxin

eIR

(D)

(im

media

tere

lease)

Venla

faxin

eX

R(C

)(e

xte

nded

rele

ase)

Pill

s:

37.5

,75,

and

150

mg

Recom

mendatio

n:

sta

rtw

ith

adose

of

37.5

mg/d

ay

for

1-2

weeks,

incre

ase

to75

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+37.5

mg/d

ay

each

week)

acco

rdin

gto

clin

icalre

sponse

and

tole

rance

untilth

em

axim

um

dose

of

112.5

mg/d

ay,

accord

ing

toage

and

weig

ht.

Imm

edia

tere

lease:

2daily

doses.

Ext

ended

rele

ase:

sin

gle

dose

(in

the

morn

ing).

Recom

mendation:

sta

rtw

ith

adose

of

37.5

mg/d

ay

for

1w

eek,

incre

ase

to75

mg/d

ay

and

wait

for

thera

peutic

response

(4-6

weeks),

with

incre

ases

indose

(+37.5

mg/d

ay

each

week)

accord

ing

toclin

icalre

sponse

and

tole

rance

untilth

em

axi

mum

dose

of

225

mg/d

ay,

accord

ing

toage

and

weig

ht.

Imm

edia

tere

lease:

2daily

doses.

Ext

ended

rele

ase:

sin

gle

dose

(in

the

morn

ing).

-M

inim

um

effects

p450

-F

requent

withdra

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studies have demonstrated that the benefits of treatinganxiety disorders largely outweigh the potential risksrelated to the increase of suicidal ideation, which, althoughserious, is a rare event in the treatment of patients withanxiety disorders.186 Nevertheless we underscore theneed to monitor continuously suicidal thoughts and suicidalbehaviors in this population.

There is a lack of consistent evidence regarding thebest way to deal with refractory anxiety disorders or thebest sequence of treatments to be applied. Overall, therecommendation is to optimize the medication dosage,since some patients only respond at higher doses (e.g.,slow metabolizers, OCD patients). If there is no responseafter 4 to 6 weeks of treatment and after the dosageoptimization, it is possible to: 1) change medicationswithin the same class (e.g., fluoxetine for sertraline) or 2)change the previous medication for another one from adifferent class (e.g., fluoxetine for venlafaxine).187

In public health systems, specialized treatment isrecommended in cases in which: 1) patients have shownrefractoriness to two previous therapeutic alternatives; 2)patients have severe chronic disorders, including highlevel of impairment, unusually frequent avoidance beha-viors and agoraphobia that do not respond to psycho-tropic and clearly require behavioral therapy or CBT; and3) patients present persistent suicidal ideation.

Preschool children treatment and prevention

Most of the currently available evidence regarding thetreatment of pediatric anxiety disorders is based onstudies with school-aged children. However, there is acurrent trend to offer treatment for younger children(preschoolers), hoping that earlier diagnoses may pre-vent later psychiatric disorders. Parental training withCBT protocols and the treatment of mood and anxietydisorders in clinically-ill parents are suggested by someauthors.188 Although scarce, there is promising evidencethat treatments based on existing therapies (CBT,parental training, and pharmacotherapy), adapted to at-risk populations, i.e., highly symptomatic children, but stillnot meeting criteria for the diagnosis of anxiety disorders,or children with first-degree relatives diagnosed withanxiety disorders, result in preventing and reducing theseverity of these disorders.189

This is a general overview about pediatric anxietydisorders. More specific and comprehensive reviewsabout the following topics can be found in the literature:prevalence,15,18-20 behavioral inhibition,190-192 behavioralgenetics,48,52 genetics,55,56,193,194 gene vs. environmentinterplay,52,70 pathophysiology,31,71 neural substrates,71

normal development of fears,195 psychopharmacologicaltreatment,196-198 and CBT.164,199-201

Conclusions

Anxiety disorders are prevalent, associated with anumber of negative life outcomes, and currently under-recognized and under-treated. The etiology involves bothgenes and environmental factors in a complex interplay.

Pathophysiology is still in its infancy, but some brainregions such as the amygdala and the prefrontal cortexpotentially play a key role to explain individual differencesrelated to fear and anxiety. The diagnosis is clinical andinvolves clinical interviews with the child, parents, andteachers. Treatment is effective using medication, CBT,or a combination of strategies.

Disclosure

Giovanni Abrahao Salum receives a post-doctoral fellow-ship from Coordenacao de Aperfeicoamento de Pessoalde Nıvel Superior (CAPES) and Fundacao de Amparo aPesquisa do Estado do Rio Grande do Sul (FAPERGS).Diogo Araujo DeSouza receives a doctoral fellowshipfrom Conselho Nacional de Desenvolvimento Cientıfico eTecnologico (CNPq). Maria Conceicao do Rosarioreceives research support from Brazilian governmentinstitutions (CNPq) and has worked in the last 5 years asa speaker for the companies Novartis and Shire. DanielPine declares no potential conflicts of interest. Gisele GusManfro receives research support from Brazilian govern-ment institutions (CNPq, FAPERGS and Fundo deIncentivo a Pesquisa - Hospital de Clınicas de PortoAlegre - FIPE-HCPA).

References

1 Woodward LJ, Fergusson DM. Life course outcomes of youngpeople with anxiety disorders in adolescence. J Am Acad ChildAdolesc Psychiatry. 2001;40:1086-93.

2 Essau CA, Conradt J, Petermann F. Frequency, comorbidity, andpsychosocial impairment of anxiety disorders in German adoles-cents. J Anxiety Disord. 2000;14:263-79.

3 Ezpeleta L, Keeler G, Erkanli A, Costello EJ, Angold A.Epidemiology of psychiatric disability in childhood and adolescence.J Child Psychol Psychiatry. 2001;42:901-14.

4 Balazs J, Miklosi M, Kereszteny A, Hoven CW, Carli V, WassermanC, et al. Adolescent subthreshold-depression and anxiety: psycho-pathology, functional impairment and increased suicide risk. J ChildPsychol Psychiatry. 2013;54:670-7.

5 Last CG, Hansen C, Franco N. Anxious children in adulthood: aprospective study of adjustment. J Am Acad Child AdolescPsychiatry. 1997;36:645-52.

6 Olatunji BO, Cisler JM, Tolin DF. Quality of life in the anxietydisorders: a meta-analytic review. Clin Psychol Rev. 2007;27:572-81.

7 Nock MK, Hwang I, Sampson NA, Kessler RC. Mental disorders,comorbidity and suicidal behavior: results from the NationalComorbidity Survey Replication. Mol Psychiatry. 2010;15:868-76.

8 Roest AM, Martens EJ, de Jonge P, Denollet J. Anxiety and risk ofincident coronary heart disease: a meta-analysis. J Am Coll Cardiol.2010;56:38-46.

9 Baldwin DS, Pallanti S, Zwanzger P. Developing a Europeanresearch network to address unmet needs in anxiety disorders.Neurosci Biobehav Rev. 2013 Jan 10. [Epub ahead of print]

10 Ranta K, Kaltiala-Heino R, Rantanen P, Marttunen M. Social phobiain Finnish general adolescent population: prevalence, comorbidity,individual and family correlates, and service use. Depress Anxiety.2009;26:528-36.

11 Merikangas KR, He JP, Brody D, Fisher PW, Bourdon K, KoretzDS. Prevalence and treatment of mental disorders among USchildren in the 2001-2004 NHANES. Pediatrics. 2010;125:75-81.

12 Chavira DA, Stein MB, Bailey K, Stein MT. Child anxiety in primarycare: prevalent but untreated. Depress Anxiety. 2004;20:155-64.

13 Wren FJ, Scholle SH, Heo J, Comer DM. Pediatric mood andanxiety syndromes in primary care: who gets identified? Int JPsychiatry Med. 2003;33:1-16.

GA Salum et al.S16


14 Rutter M. Research review: child psychiatric diagnosis andclassification: concepts, findings, challenges and potential. J ChildPsychol Psychiatry. 2011;52:647-60.

15 Beesdo-Baum K, Knappe S. Developmental epidemiology ofanxiety disorders. Child Adolesc Psychiatr Clin N Am.2012;21:457-78.

16 Merikangas KR, He JP, Burstein M, Swanson SA, Avenevoli S, CuiL, et al. Lifetime prevalence of mental disorders in U.S. adoles-cents: results from the National Comorbidity Survey Replication--Adolescent Supplement (NCS-A). J Am Acad Child AdolescPsychiatry. 2010;49:980-9.

17 Rapee RM, Schniering CA, Hudson JL. Anxiety disorders duringchildhood and adolescence: origins and treatment. Annu Rev ClinPsychol. 2009;5:311-41.

18 Costello EJ, Egger HL, Angold A. The developmental epidemiologyof anxiety disorders: phenomenology, prevalence, and comorbidity.Child Adolesc Psychiatr Clin N Am. 2005;14:631-48.

19 Beesdo K, Knappe S, Pine DS. Anxiety and anxiety disorders inchildren and adolescents: developmental issues and implicationsfor DSM-V. Psychiatr Clin North Am. 2009;32:483-524.

20 Baxter AJ, Scott KM, Vos T, Whiteford HA. Global prevalence ofanxiety disorders: a systematic review and meta-regression.Psychol Med. 2013;43:897-910.

21 Somers JM, Goldner EM, Waraich P, Hsu L. Prevalence andincidence studies of anxiety disorders: a systematic review of theliterature. Can J Psychiatry. 2006;51:100-13.

22 Adornetto C, Suppiger A, In-Albon T, Neuschwander M, SchneiderS. Concordances and discrepancies between ICD-10 and DSM-IVcriteria for anxiety disorders in childhood and adolescence. ChildAdolesc Psychiatry Ment Health. 2012;6:40.

23 Salum GA, Isolan LR, Bosa VL, Tocchetto AG, Teche SP, Schuch I,et al. The multidimensional evaluation and treatment of anxiety inchildren and adolescents: rationale, design, methods and prelimin-ary findings. Rev Bras Psiquiatr. 2011;33:181-95.

24 Baxter AJ, Charlson FJ, Somerville AJ, Whiteford HA. Mentaldisorders as risk factors: assessing the evidence for the GlobalBurden of Disease Study. BMC Med. 2011;9:134.

25 Anselmi L, Fleitlich-Bilyk B, Menezes AM, Araujo CL, Rohde LA.Prevalence of psychiatric disorders in a Brazilian birth cohort of 11-year-olds. Soc Psychiatry Psychiatr Epidemiol. 2010;45:135-42.

26 Fleitlich-Bilyk B, Goodman R. Prevalence of child and adolescentpsychiatric disorders in southeast Brazil. J Am Acad Child AdolescPsychiatry. 2004;43:727-34.

27 Craske MG. Origins of phobias and anxiety disorders: why morewomen than men? Amsterdam: Elsevier; 2003.

28 American Psychiatric Association. Diagnostic and statistical manualof mental disorders - DSM-IV-TRH. 4th ed. Arlington: AmericanPsychiatric Publishing; 1994.

29 Gregory AM, Caspi A, Moffitt TE, Koenen K, Eley TC, Poulton R.Juvenile mental health histories of adults with anxiety disorders. AmJ Psychiatry. 2007;164:301-8.

30 Pine DS, Klein RG. Anxiety disorders. In: Rutter M, Bishop DVM,Pine DS, Scott S, Stevenson J, Taylor E, Thapar A , editors.Rutter’s child and adolescent psychiatry. 5th ed. Oxford: BlackwellPublishing Ltd; 2009. p. 628-647.

31 Pine DS. Research review: a neuroscience framework for pediatricanxiety disorders. J Child Psychol Psychiatry. 2007;48:631-48.

32 Wittchen HU, Lieb R, Pfister H, Schuster P. The waxing and waningof mental disorders: evaluating the stability of syndromes of mentaldisorders in the population. Compr Psychiatry. 2000;41:122-32.

33 Kessler RC, Avenevoli S, Costello EJ, Georgiades K, Green JG,Gruber MJ, et al. Prevalence, persistence, and sociodemographiccorrelates of DSM-IV disorders in the National Comorbidity SurveyReplication Adolescent Supplement. Arch Gen Psychiatry.2012;69:372-80.

34 Pine DS, Cohen P, Gurley D, Brook J, Ma Y. The risk for early-adulthood anxiety and depressive disorders in adolescents withanxiety and depressive disorders. Arch Gen Psychiatry.1998;55:56-64.

35 Copeland WE, Shanahan L, Costello EJ, Angold A. Childhood andadolescent psychiatric disorders as predictors of young adultdisorders. Arch Gen Psychiatry. 2009;66:764-72.

36 Bittner A, Egger HL, Erkanli A, Jane Costello E, Foley DL, Angold A.What do childhood anxiety disorders predict? J Child PsycholPsychiatry. 2007;48:1174-83.

37 Angst J, Vollrath M. The natural history of anxiety disorders. ActaPsychiatr Scand. 1991;84:446-52.

38 Beesdo K, Pine DS, Lieb R, Wittchen HU. Incidence and riskpatterns of anxiety and depressive disorders and categorization ofgeneralized anxiety disorder. Arch Gen Psychiatry. 2010;67:47-57.

39 Last CG, Perrin S, Hersen M, Kazdin AE. A prospective study ofchildhood anxiety disorders. J Am Acad Child Adolesc Psychiatry.1996;35:1502-10.

40 Pine DS, Cohen P, Brook J. Adolescent fears as predictors ofdepression. Biol Psychiatry. 2001;50:721-4.

41 Kim-Cohen J, Caspi A, Moffitt TE, Harrington H, Milne BJ, PoultonR. Prior juvenile diagnoses in adults with mental disorder:developmental follow-back of a prospective-longitudinal cohort.Arch Gen Psychiatry. 2003;60:709-17.

42 Colman I, Wadsworth ME, Croudace TJ, Jones PB. Forty-yearpsychiatric outcomes following assessment for internalizing dis-order in adolescence. Am J Psychiatry. 2007;164:126-33.

43 Scholten WD, Batelaan NM, van Balkom AJ, Wjh Penninx B, SmitJH, van Oppen P. Recurrence of anxiety disorders and itspredictors. J Affect Disord. 2013;147:180-5.

44 Insel TR. Disruptive insights in psychiatry: transforming a clinicaldiscipline. J Clin Invest. 2009;119:700-5.

45 Insel TR, Quirion R. Psychiatry as a clinical neuroscience discipline.JAMA. 2005;294:2221-4.

46 Levitt P, March J. NIMH Council Workgroup on Neurodevelopment:Update on Activities and Workgroup Recommendations. Bethesda,MD: 2008.

47 Skre I, Onstad S, Edvardsen J, Torgersen S, Kringlen E. A familystudy of anxiety disorders: familial transmission and relationship tomood disorder and psychoactive substance use disorder. ActaPsychiatr Scand. 1994;90:366-74.

48 Gregory AM, Eley TC. Genetic influences on anxiety in children:what we’ve learned and where we’re heading. Clin Child FamilyPsychol Rev. 2007;10:199-212.

49 Hettema JM, Neale MC, Kendler KS. A review and meta-analysis ofthe genetic epidemiology of anxiety disorders. American JPsychiatry. 2001;158:1568-78.

50 Topolski TD, Hewitt JK, Eaves L, Meyer JM, Silberg JL, Simonoff E,et al. Genetic and environmental influences on ratings of manifestanxiety by parents and children. J Anxiety Disord. 1999;13:371-97.

51 Hettema JM, Prescott CA, Myers JM, Neale MC, Kendler KS. Thestructure of genetic and environmental risk factors for anxietydisorders in men and women. Arch Gen Psychiatry. 2005;62:182-9.

52 Franic S, Middeldorp CM, Dolan CV, Ligthart L, Boomsma DI.Childhood and adolescent anxiety and depression: beyond herit-ability. J Am Acad Child Adolesc Psychiatry. 2010;49:820-9.

53 Rommelse NN, Franke B, Geurts HM, Hartman CA, Buitelaar JK.Shared heritability of attention-deficit/hyperactivity disorder andautism spectrum disorder. Eur Child Adolesc Psychiatry.2010;19:281-95.

54 Lahey BB, Van Hulle CA, Singh AL, Waldman ID, Rathouz PJ.Higher-order genetic and environmental structure of prevalentforms of child and adolescent psychopathology. Arch GenPsychiatry. 2011;68:181-9.

55 Sakolsky DJ, McCracken JT, Nurmi EL. Genetics of pediatric anxietydisorders. Child Adolesc Psychiatr Clin N Am. 2012;21:479-500.

56 McGrath LM, Weill S, Robinson EB, Macrae R, Smoller JW.Bringing a developmental perspective to anxiety genetics. DevPsychopathol. 2012;24:1179-93.

57 Erhardt A, Czibere L, Roeske D, Lucae S, Unschuld PG, Ripke S,et al. TMEM132D, a new candidate for anxiety phenotypes:evidence from human and mouse studies. Mol Psychiatry.2011;16:647-63.

58 Otowa T, Tanii H, Sugaya N, Yoshida E, Inoue K, Yasuda S, et al.Replication of a genome-wide association study of panic disorder ina Japanese population. J Hum Genet. 2010;55:91-6.

59 Otowa T, Yoshida E, Sugaya N, Yasuda S, Nishimura Y, Inoue K,et al. Genome-wide association study of panic disorder in theJapanese population. J Hum Genet. 2009;54:122-6.



60 Stewart SE, Yu D, Scharf JM, Neale BM, Fagerness JA, MathewsCA, et al. Genome-wide association study of obsessive-compulsivedisorder. Mol Psychiatry. 2012 Aug 14. [Epub ahead of print]

61 Logue MW, Baldwin C, Guffanti G, Melista E, Wolf EJ, Reardon AF,et al. A genome-wide association study of post-traumatic stressdisorder identifies the retinoid-related orphan receptor alpha(RORA) gene as a significant risk locus. Mol Psychiatry. 2012Aug 7. [Epub ahead of print]

62 Gregersen N, Dahl HA, Buttenschon HN, Nyegaard M, HedemandA, Als TD, et al. A genome-wide study of panic disorder suggeststhe amiloride-sensitive cation channel 1 as a candidate gene. Eur JHum Genet. 2012;20:84-90.

63 Otowa T, Kawamura Y, Nishida N, Sugaya N, Koike A, Yoshida E,et al. Meta-analysis of genome-wide association studies for panicdisorder in the Japanese population. Transl Psychiatry.2012;2:e186.

64 Kawamura Y, Otowa T, Koike A, Sugaya N, Yoshida E, Yasuda S,et al. A genome-wide CNV association study on panic disorder in aJapanese population. J Hum Genet. 2011;56:852-6.

65 Lau JY, Gregory AM, Goldwin MA, Pine DS, Eley TC. Assessinggene-environment interactions on anxiety symptom subtypesacross childhood and adolescence. Dev Psychopathol.2007;19:1129-46.

66 Hicks BM, DiRago AC, Iacono WG, McGue M. Gene-environmentinterplay in internalizing disorders: consistent findings across sixenvironmental risk factors. J Child Psychol Psychiatry.2009;50:1309-17.

67 Narusyte J, Neiderhiser JM, D’Onofrio BM, Reiss D, Spotts EL,Ganiban J, et al. Testing different types of genotype-environmentcorrelation: an extended children-of-twins model. Dev Psychol.2008;44:1591-603.

68 Kendler KS, Baker JH. Genetic influences on measures of theenvironment: a systematic review. Psychol Med. 2007;37:615-26.

69 Kendler KS. Parenting: a genetic-epidemiologic perspective. Am JPsychiatry. 1996;153:11-20.

70 Rutter M, Moffitt TE, Caspi A. Gene-environment interplay andpsychopathology: multiple varieties but real effects. J Child PsycholPsychiatry. 2006;47:226-61.

71 Blackford JU, Pine DS. Neural substrates of childhood anxietydisorders: a review of neuroimaging findings. Child AdolescPsychiatr Clin N Am. 2012;21:501-25.

72 Shechner T, Britton JC, Perez-Edgar K, Bar-Haim Y, Ernst M, FoxNA, et al. Attention biases, anxiety, and development: toward oraway from threats or rewards? Depress Anxiety. 2012;29:282-94.

73 Britton JC, Lissek S, Grillon C, Norcross MA, Pine DS.Development of anxiety: the role of threat appraisal and fearlearning. Depress Anxiety. 2011;28:5-17.

74 Lissek S. Toward an account of clinical anxiety predicated on basic,neurally mapped mechanisms of Pavlovian fear-learning: the casefor conditioned overgeneralization. Depress Anxiety. 2012;29:257-63.

75 Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. Neurogenesisand generalization: a new approach to stratify and treat anxietydisorders. Nat Neurosci. 2012;15:1613-20.

76 Guyer AE, Lau JY, McClure-Tone EB, Parrish J, Shiffrin ND,Reynolds RC, et al. Amygdala and ventrolateral prefrontal cortexfunction during anticipated peer evaluation in pediatric socialanxiety. Arch Gen Psychiatry. 2008;65:1303-12.

77 Guyer AE, Choate VR, Detloff A, Benson B, Nelson EE, Perez-Edgar K, et al. Striatal functional alteration during incentiveanticipation in pediatric anxiety disorders. Am J Psychiatry.2012;169:205-12.

78 Guyer AE, Nelson EE, Perez-Edgar K, Hardin MG, Roberson-NayR, Monk CS, et al. Striatal functional alteration in adolescentscharacterized by early childhood behavioral inhibition. J Neurosci.2006;26:6399-405.

79 Mana S, Paillere Martinot ML, Martinot JL. Brain imaging findings inchildren and adolescents with mental disorders: a cross-sectionalreview. Eur Psychiatry. 2010;25:345-54.

80 Milad MR, Rauch SL. Obsessive-compulsive disorder: beyondsegregated cortico-striatal pathways. Trends Cogn Sci. 2012;16:43-51.

81 Rapee RM. Potential role of childrearing practices in the develop-ment of anxiety and depression. Clin Psychol Rev. 1997;17:47-67.

82 McLeod BD, Wood JJ, Weisz JR. Examining the associationbetween parenting and childhood anxiety: a meta-analysis. ClinPsychol Rev. 2007;27:155-72.

83 Allen JL, Rapee RM, Sandberg S. Severe life events and chronicadversities as antecedents to anxiety in children: a matched controlstudy. J Abnorm Child Psychol. 2008;36:1047-56.

84 Eley TC, Stevenson J. Specific life events and chronic experiencesdifferentially associated with depression and anxiety in young twins.J Abnorm Child Psychol. 2000;28:383-94.

85 Murray L, Creswell C, Cooper PJ. The development of anxietydisorders in childhood: an integrative review. Psychol Med.2009;39:1413-23.

86 Otowa T, Gardner CO, Kendler KS, Hettema JM. Parenting and riskfor mood, anxiety and substance use disorders: a study inpopulation-based male twins. Soc Psychiatry Psychiatr Epidemiol.2013 Jan 24. [Epub ahead of print]

87 de Rosnay M, Cooper PJ, Tsigaras N, Murray L. Transmission ofsocial anxiety from mother to infant: an experimental study using asocial referencing paradigm. Behav Res Ther. 2006;44:1165-75.

88 Gerull FC, Rapee RM. Mother knows best: effects of maternalmodelling on the acquisition of fear and avoidance behaviour intoddlers. Behav Res Ther. 2002;40:279-87.

89 Murray L, de Rosnay M, Pearson J, Bergeron C, Schofield E,Royal-Lawson M, et al. Intergenerational transmission of socialanxiety: the role of social referencing processes in infancy. ChildDev. 2008;79:1049-64.

90 Field AP. Is conditioning a useful framework for understanding thedevelopment and treatment of phobias? Clin Psychol Rev.2006;26:857-75.

91 Field AP, Lawson J. Fear information and the development of fearsduring childhood: effects on implicit fear responses and behaviouralavoidance. Behav Res Ther. 2003;41:1277-93.

92 Kraemer HC, Kazdin AE, Offord DR, Kessler RC, Jensen PS,Kupfer DJ. Coming to terms with the terms of risk. Arch GenPsychiatry. 1997;54:337-43.

93 Kraemer HC, Stice E, Kazdin A, Offord D, Kupfer D. How do riskfactors work together? Mediators, moderators, and independent,overlapping, and proxy risk factors. Am J Psychiatry. 2001;158:848-56.

94 Kendler KS. ‘‘A gene for...’’: the nature of gene action in psychiatricdisorders. Am J Psychiatry. 2005;162:1243-52.

95 Kendler KS. Preparing for gene discovery: a further agenda forpsychiatry. Arch Gen Psychiatry. 1999;56:554-5.

96 Kendler KS. Explanatory models for psychiatric illness. Am JPsychiatry. 2008;165:695-702.

97 Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, et al.Research Domain Criteria (RDoC): toward a new classificationframework for research on mental disorders. Am J Psychiatry.2010;167:748-51.

98 Sanislow CA, Pine DS, Quinn KJ, Kozak MJ, Garvey MA, HeinssenRK, et al. Developing constructs for psychopathology research:research domain criteria. J Abnorm Psychol. 2010;119:631-9.

99 Coghill D, Sonuga-Barke EJ. Annual research review: categoriesversus dimensions in the classification and conceptualisation ofchild and adolescent mental disorders--implications of recentempirical study. J Child Psychol Psychiatry. 2012;53:469-89.

100 Skarin K. Cognitive and contextual determinants of stranger fear insix- and eleven-month-old infants. Child Dev. 1977;48:537-44.

101 Thompson RA, Limber SP. ‘‘Social anxiety’’ in infancy: stranger andseparation reactions. In: Leitenberg H, editor. Handbook of socialand evaluation anxiety. New York: Plenum Press; 1990. p. 85-137.

102 Kagan J, Snidman N, Zentner M, Peterson E. Infant temperamentand anxious symptoms in school age children. Dev Psychopathol.1999;11:209-24.

103 Clauss JA, Blackford JU. Behavioral inhibition and risk fordeveloping social anxiety disorder: a meta-analytic study. J AmAcad Child Adolesc Psychiatry. 2012;51:1066-75.

104 Degnan KA, Almas AN, Fox NA. Temperament and the environ-ment in the etiology of childhood anxiety. J Child PsycholPsychiatry. 2010;51:497-517.

105 Noel VA, Francis SE. A meta-analytic review of the role of childanxiety sensitivity in child anxiety. J Abnorm Child Psychol.2011;39:721-33.

GA Salum et al.S18


106 Olatunji BO, Wolitzky-Taylor KB. Anxiety sensitivity and the anxietydisorders: a meta-analytic review and synthesis. Psychol Bull.2009;135:974-99.

107 Salum GA, Alvarenga PG, Manfro GG. Transtornos de ansiedade etranstorno obsessivo-compulsivo. In: Polanczyk GV, LamberteMTMR, editors. Psiquiatria da infancia e adolescencia. SaoPaulo: Manole; 2012.

108 Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN,Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or acombination in childhood anxiety. N Engl J Med. 2008;359:2753-66.

109 Angold A, Costello EJ, Erkanli A. Comorbidity. J Child PsycholPsychiatry. 1999;40:57-87.

110 Wolitzky-Taylor K, Bobova L, Zinbarg RE, Mineka S, Craske MG.Longitudinal investigation of the impact of anxiety and mooddisorders in adolescence on subsequent substance use disorderonset and vice versa. Addict Behav. 2012;37:982-5.

111 Moffitt TE, Harrington H, Caspi A, Kim-Cohen J, Goldberg D,Gregory AM, et al. Depression and generalized anxiety disorder:cumulative and sequential comorbidity in a birth cohort followedprospectively to age 32 years. Arch Gen Psychiatry. 2007;64:651-60.

112 Gandhi B, Cheek S, Campo JV. Anxiety in the pediatric medicalsetting. Child Adolesc Psychiatr Clin N Am. 2012;21:643-53.

113 Brasil HHA. Development of the Brazilian version of K-SADS-PL(Schedule for Affective Disorders and Schizophrenia for SchoolAged Children Present and Lifetime Version) and study ofpsychometric properties [dissertation]. Sao Paulo: UniversidadeFederal de Sao Paulo; 2003.

114 Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al.Schedule for Affective Disorders and Schizophrenia for School-AgeChildren-Present and Lifetime Version (K-SADS-PL): initial relia-bility and validity data. J Am Acad Child Adolesc Psychiatry.1997;36:980-8.

115 Polanczyk GV, Eizirik M, Aranovich V, Denardin D, da Silva TL,da Conceicao TV, et al. Interrater agreement for the schedulefor affective disorders and schizophrenia epidemiological versionfor school-age children (K-SADS-E). Rev Bras Psiquiatr. 2003;25:87-90.

116 Angold A, Erkanli A, Copeland W, Goodman R, Fisher PW, CostelloEJ. Psychiatric diagnostic interviews for children and adolescents: acomparative study. J Am Acad Child Adolesc Psychiatry.2012;51:506-17.

117 Goodman R, Ford T, Richards H, Gatward R, Meltzer H. TheDevelopment and Well-Being Assessment: description and initialvalidation of an integrated assessment of child and adolescentpsychopathology. J Child Psychol Psychiatry. 2000;41:645-55.

118 Souza IGS, Serra-Pinheiro MA, Mousinho R, Mattos PA. ABrazilian version of the ‘‘Children’s Interview for PsychiatricSyndromes’’ (ChIPS). J Bras Psiquiatr. 2009;58:115-8.

119 Weller EB, Weller RA, Fristad MA, Rooney MT, Schecter J.Children’s Interview for Psychiatric Syndromes (ChIPS). J Am AcadChild Adolesc Psychiatry. 2000;39:76-84.

120 Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME.NIMH Diagnostic Interview Schedule for Children Version IV (NIMHDISC-IV): description, differences from previous versions, andreliability of some common diagnoses. J Am Acad Child AdolescPsychiatry. 2000;39:28-38.

121 Reich W. Diagnostic interview for children and adolescents (DICA).J Am Acad Child Adolesc Psychiatry. 2000;39:59-66.

122 Welner Z, Reich W, Herjanic B, Jung KG, Amado H. Reliability,validity, and parent-child agreement studies of the DiagnosticInterview for Children and Adolescents (DICA). J Am Acad ChildAdolesc Psychiatry. 1987;26:649-53.

123 Sherrill JT, Kovacs M. Interview schedule for children andadolescents (ISCA). J Am Acad Child Adolesc Psychiatry.2000;39:67-75.

124 Lyneham HJ, Abbott MJ, Rapee RM. Interrater reliability of theAnxiety Disorders Interview Schedule for DSM-IV: child and parentversion. J Am Acad Child Adolesc Psychiatry. 2007;46:731-6.

125 Silverman WK, Saavedra LM, Pina AA. Test-retest reliability ofanxiety symptoms and diagnoses with the Anxiety DisordersInterview Schedule for DSM-IV: child and parent versions. J AmAcad Child Adolesc Psychiatry. 2001;40:937-44.

126 Angold A, Costello EJ. The Child and Adolescent PsychiatricAssessment (CAPA). J Am Acad Child Adolesc Psychiatry.2000;39:39-48.

127 Angold A, Prendergast M, Cox A, Harrington R, Simonoff E, RutterM. The Child and Adolescent Psychiatric Assessment (CAPA).Psychol Med. 1995;25:739-53.

128 Egger HL, Erkanli A, Keeler G, Potts E, Walter BK, Angold A. Test-retest reliability of the Preschool Age Psychiatric Assessment(PAPA). J Am Acad Child Adolesc Psychiatry. 2006;45:538-49.

129 Merikangas K, Avenevoli S, Costello J, Koretz D, Kessler RC.National comorbidity survey replication adolescent supplement(NCS-A): I. background and measures. J Am Acad Child AdolescPsychiatry. 2009;48:367-9.

130 Biaggio AMB, Spielberger CD. [Manual of the Portuguese form ofthe STAI]. Rio de Janeiro: CEPA; 1983.

131 Spielberger CD. Manual for the State-Trait Anxiety Inventory forChildren. Palo Alto: Consulting Psychologist Press; 1973.

132 Gorayeb MAM, Gorayeb R. [Revised Children’s Manifest AnxietyScale (RCMAS) adapt to Portuguese in Brazil]. Temas Psicol.2008;16:35-45.

133 Reynolds CR, Richmond BO. What I think and feel: a revisedmeasure of children’s manifest anxiety. J Abnorm Child Psychol.1997;25:15-20.

134 Beck JS, Beck AT, Jolly JB, Steer RA. Beck Youth Inventories forchildren and adolescents: manual. 2nd ed. San Antonio: HarcourtAssessment, Inc; 2005.

135 The Pediatric Anxiety Rating Scale (PARS): development andpsychometric properties. J Am Acad Child Adolesc Psychiatry.2002;41:1061-9.

136 Caporino NE, Brodman DM, Kendall PC, Albano AM, Sherrill J,Piacentini J, et al. Defining treatment response and remission inchild anxiety: signal detection analysis using the pediatric anxietyrating scale. J Am Acad Child Adolesc Psychiatry. 2013;52:57-67.

137 Birmaher B, Brent DA, Chiappetta L, Bridge J, Monga S, BaugherM. Psychometric properties of the Screen for Child Anxiety RelatedEmotional Disorders (SCARED): a replication study. J Am AcadChild Adolesc Psychiatry. 1999;38:1230-6.

138 Birmaher B, Khetarpal S, Brent D, Cully M, Balach L, Kaufman J,et al. The Screen for Child Anxiety Related Emotional Disorders(SCARED): scale construction and psychometric characteristics. JAm Acad Child Adolesc Psychiatry. 1997;36:545-53.

139 Desousa DA, Salum GA, Isolan LR, Manfro GG. Sensitivity andspecificity of the screen for Child Anxiety Related EmotionalDisorders (SCARED): a community-based study. Child PsychiatryHum Dev. 2013;44:391-9.

140 Isolan L, Salum GA, Osowski AT, Amaro E, Manfro GG.Psychometric properties of the Screen for Child Anxiety RelatedEmotional Disorders (SCARED) in Brazilian children and adoles-cents. J Anxiety Disord. 2011;25:741-8.

141 DeSousa DA, Petersen CS, Behs R, Manfro GG, Koller SH.Brazilian Portuguese version of the Spence Children’s AnxietyScale (SCAS-Brasil). Trends Psychiatry Psychother. 2012;34:147-53.

142 Spence SH. A measure of anxiety symptoms among children.Behav Res Ther. 1998;36:545-66.

143 Spence SH. Structure of anxiety symptoms among children: aconfirmatory factor-analytic study. J Abnorm Psychol.1997;106:280-97.

144 March JS, Parker JD, Sullivan K, Stallings P, Conners CK. TheMultidimensional Anxiety Scale for Children (MASC): factorstructure, reliability, and validity. J Am Acad Child AdolescPsychiatry. 1997;36:554-65.

145 Masia-Warner C, Storch EA, Pincus DB, Klein RG, Heimberg RG,Liebowitz MR. The Liebowitz social anxiety scale for children andadolescents: an initial psychometric investigation. J Am Acad ChildAdolesc Psychiatry. 2003;42:1076-84.

146 Gauer GC, Picon P, Davoglio TR, Silva LM, Beidel DC.Psychometric characteristics of the Brazilian Portuguese versionof Social Phobia and Anxiety Inventory for Children (SPAI-C).Psico. 2009;40:354-8.

147 Gauer GJ, Picon P, Vasconcellos SJ, Turner SM, Beidel DC.Validation of the Social Phobia and Anxiety Inventory for Children(SPAI-C) in a sample of Brazilian children. Braz J Med Biol Res.2005;38:795-800.



148 Scaini S, Battaglia M, Beidel DC, Ogliari A. A meta-analysis of thecross-cultural psychometric properties of the Social Phobia andAnxiety Inventory for Children (SPAI-C). J Anxiety Disord.2012:182-8.

149 Beidel DC, Turner SM, Morris TL. A new inventory to assesschildhood social anxiety and phobia: The Social Phobia and AnxietyInventory for Children. Psychol Assess. 1995;7:73-9.

150 Freeman J, Flessner CA, Garcia A. The Children’s Yale-BrownObsessive Compulsive Scale: reliability and validity for use among5 to 8 year olds with obsessive-compulsive disorder. J AbnormChild Psychol. 2011;39:877-83.

151 Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA,Goodman WK, et al. Children’s Yale-Brown Obsessive CompulsiveScale: reliability and validity. J Am Acad Child Adolesc Psychiatry.1997;36:844-52.

152 Storch EA, Murphy TK, Adkins JW, Lewin AB, Geffken GR, JohnsNB, et al. The children’s Yale-Brown obsessive-compulsive scale:psychometric properties of child- and parent-report formats. JAnxiety Disord. 2006;20:1055-70.

153 Rosario-Campos MC, Miguel EC, Quatrano S, Chacon P, Ferrao Y,Findley D, et al. The Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS): an instrument for assessingobsessive-compulsive symptom dimensions. Mol Psychiatry.2006;11:495-504.

154 Ollendick TH. Reliability and validity of the Revised Fear SurgerySchedule for Children (FSSC-R). Behav Res Ther. 1983;21:685-92.

155 Masi G, Pari C, Millepiedi S. Pharmacological treatment options forpanic disorder in children and adolescents. Expert OpinPharmacother. 2006;7:545-54.

156 Pine DS, Cohen JA. Trauma in children and adolescents: risk andtreatment of psychiatric sequelae. Biol Psychiatry. 2002;51:519-31.

157 Cohen JA, Bukstein O, Walter H, Benson SR, Chrisman A,Farchione TR, et al. Practice parameter for the assessment andtreatment of children and adolescents with posttraumatic stressdisorder. J Am Acad Child Adolesc Psychiatry. 2010;49:414-30.

158 Ipser JC, Stein DJ, Hawkridge S, Hoppe L. Pharmacotherapy foranxiety disorders in children and adolescents. Cochrane DatabaseSyst Rev. 2009:CD005170.

159 DeVeaugh-Geiss J, Moroz G, Biederman J, Cantwell D, FontaineR, Greist JH, et al. Clomipramine hydrochloride in childhood andadolescent obsessive-compulsive disorder--a multicenter trial. JAm Acad Child Adolesc Psychiatry. 1992;31:45-9.

160 Uthman OA, Abdulmalik J. Comparative efficacy and acceptabilityof pharmacotherapeutic agents for anxiety disorders in children andadolescents: a mixed treatment comparison meta-analysis. CurrMed Res Opin. 2010;26:53-9.

161 Connolly SD, Suarez L, Sylvester C. Assessment and treatment ofanxiety disorders in children and adolescents. Curr Psychiatry Rep.2011;13:99-110.

162 Graae F, Milner J, Rizzotto L, Klein RG. Clonazepam in childhoodanxiety disorders. J Am Acad Child Adolesc Psychiatry.1994;33:372-6.

163 O’Kearney RT, Anstey KJ, von Sanden C. Behavioural andcognitive behavioural therapy for obsessive compulsive disorderin children and adolescents. Cochrane Database Syst Rev.2006:CD004856.

164 Reynolds S, Wilson C, Austin J, Hooper L. Effects of psychotherapyfor anxiety in children and adolescents: a meta-analytic review. ClinPsychol Rev. 2012;32:251-62.

165 Davis TE, 3rd, May A, Whiting SE. Evidence-based treatment ofanxiety and phobia in children and adolescents: current status andeffects on the emotional response. Clin Psychol Rev. 2011;31:592-602.

166 James A, Soler A, Weatherall R. Cognitive behavioural therapy foranxiety disorders in children and adolescents. Cochrane DatabaseSyst Rev. 2005:CD004690.

167 Alvarenga PG, Mastrorosa RS, Rosario MC. Obsessive compulsivedisorder in children and adolescents. In Rey JM, editor. IACAPAPe-Textbook of Child and Adolescent Mental Health. Geneva:International Association for Child and Adolescent Psychiatry andAllied Professions; 2012. p. 1-17.

168 Pediatric OCD Treatment Study (POTS) Team. Cognitive-behaviortherapy, sertraline, and their combination for children and adoles-cents with obsessive-compulsive disorder: the Pediatric OCD

Treatment Study (POTS) randomized controlled trial. JAMA.2004;292:1969-76.

169 Garcia AM, Sapyta JJ, Moore PS, Freeman JB, Franklin ME, MarchJS, et al. Predictors and moderators of treatment outcome in thePediatric Obsessive Compulsive Treatment Study (POTS I). J AmAcad Child Adolesc Psychiatry. 2011;49:1024-33.

170 March JS, Franklin ME, Leonard H, Garcia A, Moore P, Freeman J,et al. Tics moderate treatment outcome with sertraline but notcognitive-behavior therapy in pediatric obsessive-compulsive dis-order. Biol Psychiatry. 2007;61:344-7.

171 Rosario M, Alvarenga P, Mathis M, Leckman J. Obsessive-compulsive disorder in childhood. In: Banaschewski T, Rohde L,editors. Biological child psychiatry - recent trends and develop-ments. Basel: Karger; 2008. p. 82-94.

172 Norberg MM, Krystal JH, Tolin DF. A meta-analysis of D-cycloserine and the facilitation of fear extinction and exposuretherapy. Biol Psychiatry. 2008;63:1118-26.

173 Hakamata Y, Lissek S, Bar-Haim Y, Britton JC, Fox NA, LeibenluftE, et al. Attention bias modification treatment: a meta-analysistoward the establishment of novel treatment for anxiety. BiolPsychiatry. 2010;68:982-90.

174 Eldar S, Apter A, Lotan D, Edgar KP, Naim R, Fox NA, et al.Attention bias modification treatment for pediatric anxiety disorders:a randomized controlled trial. Am J Psychiatry. 2012;169:213-20.

175 Pittenger C, Kelmendi B, Wasylink S, Bloch MH, Coric V. Riluzoleaugmentation in treatment-refractory obsessive-compulsive disor-der: a series of 13 cases, with long-term follow-up. J ClinPsychopharmacol. 2008;28:363-7.

176 Grant JE, Kim SW, Odlaug BL. N-acetyl cysteine, a glutamate-modulating agent, in the treatment of pathological gambling: a pilotstudy. Biol Psychiatry. 2007;62:652-7.

177 Jayakody K, Gunadasa S, Hosker C. Exercise for anxiety disorders:systematic review. Br J Sports Med. 2013 Jan 7. [Epub ahead ofprint]

178 Asmundson GJ, Fetzner MG, Deboer LB, Powers MB, Otto MW,Smits JA. Let’s get physical: a contemporary review of the anxiolyticeffects of exercise for anxiety and its disorders. Depress Anxiety.2013;30:362-73.

179 Larun L, Nordheim LV, Ekeland E, Hagen KB, Heian F. Exercise inprevention and treatment of anxiety and depression among childrenand young people. Cochrane Database Syst Rev. 2006:CD004691.

180 Pittler MH, Ernst E. Kava extract for treating anxiety. CochraneDatabase Syst Rev. 2003:CD003383.

181 Miyasaka LS, Atallah AN, Soares BG. Valerian for anxietydisorders. Cochrane Database Syst Rev. 2006:CD004515.

182 Miyasaka LS, Atallah AN, Soares BG. Passiflora for anxietydisorder. Cochrane Database Syst Rev. 2007:CD004518.

183 Krisanaprakornkit T, Krisanaprakornkit W, Piyavhatkul N,Laopaiboon M. Meditation therapy for anxiety disorders.Cochrane Database Syst Rev. 2006:CD004998.

184 Robinson J, Biley FC, Dolk H. Therapeutic touch for anxietydisorders. Cochrane Database Syst Rev. 2007:CD006240.

185 Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D,Ritz L, et al. Evaluation of outcomes with citalopram for depressionusing measurement-based care in STAR*D: implications for clinicalpractice. Am J Psychiatry. 2006;163:28-40.

186 Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B, PincusHA, et al. Clinical response and risk for reported suicidalideation and suicide attempts in pediatric antidepressant treatment:a meta-analysis of randomized controlled trials. JAMA. 2007;297:1683-96.

187 Stein DJ, Baldwin DS, Bandelow B, Blanco C, Fontenelle LF, LeeS, et al. A 2010 evidence-based algorithm for the pharmacotherapyof social anxiety disorder. Curr Psychiatry Rep. 2010;12:471-7.

188 Gleason MM, Egger HL, Emslie GJ, Greenhill LL, Kowatch RA,Lieberman AF, et al. Psychopharmacological treatment for veryyoung children: contexts and guidelines. J Am Acad Child AdolescPsychiatry. 2007;46:1532-72.

189 Rapee RM, Kennedy SJ, Ingram M, Edwards SL, Sweeney L.Altering the trajectory of anxiety in at-risk young children. Am JPsychiatry. 2010;167:1518-25.

190 Degnan KA, Fox NA. Behavioral inhibition and anxiety disorders:multiple levels of a resilience process. Dev Psychopathol. 2007;19:729-46.

GA Salum et al.S20


191 Fox NA, Henderson HA, Marshall PJ, Nichols KE, Ghera MM.Behavioral inhibition: linking biology and behavior within a devel-opmental framework. Annu Rev Psychol. 2005;56:235-62.

192 Hirshfeld-Becker DR, Micco J, Henin A, Bloomfield A, Biederman J,Rosenbaum J. Behavioral inhibition. Depress Anxiety. 2008;25:357-67.

193 Smoller JW, Block SR, Young MM. Genetics of anxiety disorders: thecomplex road from DSM to DNA. Depress Anxiety. 2009;26:965-75.

194 Domschke K, Deckert J. Genetics of anxiety disorders - status quoand quo vadis. Curr Pharm Des. 2012;18:5691-8.

195 Gullone E. The development of normal fear: a century of research.Clin Psychol Rev. 2000;20:429-51.

196 Strawn JR, Sakolsky DJ, Rynn MA. Psychopharmacologic treat-ment of children and adolescents with anxiety disorders. ChildAdolesc Psychiatr Clin N Am. 2012;21:527-39.

197 Rynn M, Puliafico A, Heleniak C, Rikhi P, Ghalib K, Vidair H.Advances in pharmacotherapy for pediatric anxiety disorders.Depress Anxiety. 2011;28:76-87.

198 Peters TE, Connolly S. Psychopharmacologic treatment forpediatric anxiety disorders. Child Adolesc Psychiatr Clin N Am.2012;21:789-806.

199 Kar N. Cognitive behavioral therapy for the treatment of post-traumatic stress disorder: a review. Neuropsychiatr Dis Treat.2011;7:167-81.

200 Kircanski K, Peris TS, Piacentini JC. Cognitive-behavioral therapyfor obsessive-compulsive disorder in children and adolescents.Child Adolesc Psychiatr Clin N Am. 2011;20:239-54.

201 Seligman LD, Ollendick TH. Cognitive-behavioral therapy foranxiety disorders in youth. Child Adolesc Psychiatr Clin N Am.2011;20:217-38.



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Pediatric anxiety disorders: from neuroscience to evidence ... · UPDATE ARTICLE Pediatric anxiety disorders: from neuroscience to evidence-based clinical practice Giovanni Abraha˜o