AACAP-practice Parameter - Anxiety

A AC A P O F F I CI A L A C T I O N
Clinical Practice Guideline for the Assessment and

Treatment of Children and Adolescents With Anxiety
Disorders
Heather J. Walter, MD, MPH, Oscar G. Bukstein, MD, MPH, A. Reese Abright, MD,
Helene Keable, MD, Ujjwal Ramtekkar, MD, MPE, MBA,
Jane Ripperger-Suhler, MD, Carol Rockhill, MD, PhD, MPH
Anxiety disorders are among the most common psychiatric disorders in children and adolescents. As reviewed in this guideline, both cognitive-behavioral
therapy (CBT) and selective serotonin reuptake inhibitor (SSRI) medication have considerable empirical support as safe and effective short-term
treatments for anxiety in children and adolescents. Serotonin norepinephrine reuptake inhibitor (SNRI) medication has some empirical support as
an additional treatment option. In the context of a protracted severe shortage of child and adolescenttrained behavioral health specialists, research
demonstrating convenient, efficient, cost-effective, and user-friendly delivery mechanisms for safe and effective treatments for child and adolescent
anxiety disorders is an urgent priority. The comparative effectiveness of anxiety treatments, delineation of mediators and moderators of effective anxiety
treatments, long-term effects of SSRI and SNRI use in children and adolescents, and additional evaluation of the degree of suicide risk associated with
SSRIs and SNRIs remain other key research needs.
Key Words: clinical practice guideline, anxiety, child psychiatry, assessment, treatment
J Am Acad Child Adolesc Psychiatry 2020;59(10):1107–1124.
he objective of this Clinical Practice Guideline is separation anxiety during the preschool/early school-age
T to enhance the quality of care and clinical out-
comes for children and adolescents with anxiety
disorders as defined by the Diagnostic and Statistical Manual
years; specific phobias in the school-age years; social anxi-
ety in the later school-age and early adolescent years; and
generalized anxiety, panic, and agoraphobia in the later
of Mental Disorders.1 The primary aim of the guideline is to adolescent/young adult years.6 The development of an
summarize empirically based guidance about the psycho- anxiety disorder may be foreshadowed by behavioral inhi-
social and psychopharmacologic treatment of anxiety. A bition,7 autonomic hyperreactivity,8 or negative affectivity.9
secondary aim is to summarize expert-based guidance about Parent/parenting factors,10 stressful/traumatic exposures,11
the assessment of anxiety as an integral part of treatment and insecure attachment12 also may play important etio-
and the implementation of empirically based treatments in logic roles. Anxiety disorders (especially generalized anxiety)
clinical practice. are highly comorbid with each other and with other psy-
Anxiety disorders are among the most common psychiatric disorders,13,14 particularly depression15 but also
chiatric disorders in children and adolescents. At any given bipolar, attention-deficit/hyperactivity disorder (ADHD),
time, nearly 7% of youths worldwide have an anxiety dis- learning/language, behavior, obsessive-compulsive, eating,
order2; estimated lifetime prevalence in the United States and substance-related disorders. For comorbid occurrences,
approximates 20% to 30%.3,4 For specific anxiety disorders multifaceted treatment plans likely are necessary.16
among youths 13 to 18 years old, lifetime prevalence rates Although onset can be acute, the course of anxiety tends
approximate 20% for specific phobia, 9% for social anxiety, to be chronic,17 often with waxing and waning, and exhibits
8% for separation anxiety, and 2% each for agoraphobia, both homotypic (prediction of a disorder by the same dis-
panic, and generalized anxiety.3 order) and heterotypic (prediction of a disorder by a
The median age of onset of anxiety disorders approxi- different disorder) continuity.18 Likely reflecting a common
mates 11 years5; however, each anxiety disorder often (but underlying vulnerability (eg, “negative valence systems”),19
not always) onsets during a specific developmental phase: examples of heterotypic continuity are the prediction of
Journal of the American Academy of Child & Adolescent Psychiatry www.jaacap.org 1107
Volume 59 / Number 10 / October 2020
AACAP OFFICIAL ACTION
panic and depressive disorders in adolescence and adulthood conducted by the Mayo Clinic Evidence-based Practice
by separation anxiety in childhood, and the prediction of Center under contract with the Agency for Healthcare
social anxiety in adolescence and adulthood by selective Research and Quality (AHRQ).34-36 (Because selective
mutism in childhood. mutism was not included as a primary disorder in studies
The sequelae of untreated child and adolescent anxiety included in the AHRQ/Mayo review, the treatment of this
disorders are manifold, including impairments in social, disorder is not addressed in this guideline). Insofar as
educational, occupational, health, and mental health out- available, evidence from meta-analyses published since the
comes extending from childhood into adulthood.20-22 AHRQ/Mayo review are presented to support or refute the
Among adolescents with anxiety, 9% were reported AHRQ/Mayo findings.37-43
to have had suicidal ideation, and 6% made suicide Because of sparse or absent empirical evidence, clinical
attempts23; panic disorder24 and generalized anxiety dis- guidance about the assessment of anxiety disorders and
order with comorbid depression25 may convey the great- about the implementation of empirically based treatments is
est risk. based primarily upon expert opinion and consensus as
Despite the availability of effective treatments for anx- presented in chapters in leading textbooks of child and
iety,26 less than one-half of youths needing mental health adolescent psychiatry,44-61 the DSM-5,1 previously pub-
treatment receive any care, and fewer still receive evidence- lished clinical practice guidelines,62-65 and government-
based care.27-30 Better identification, assessment, and affiliated prescription drug information websites (https://
treatment of anxiety disorders by clinicians from multiple dailymed.nlm.nih.gov/dailymed/66; https://www.fda.gov/
disciplines could have a substantial impact on the individual Drugs67).
and public health burden of mental illness in children and The peer review and approval process for the draft
adolescents. guideline spanned the period February 1, 2019, to March
11, 2020, and included reviewers representing the following
OVERVIEW OF THE GUIDELINE DEVELOPMENT stakeholder groups (see end of this document for complete
PROCESS list): 1) topic experts; 2) other members of the AACAP
Authorship, Source, and Scientific Review CQI; 3) other relevant AACAP committees; 4) the AACAP
The authors of this guideline (the Guideline Writing Assembly of Regional Organizations; 5) relevant external
Group) are co-chairs and members of the AACAP organizations; and 6) AACAP members. All suggested edits
Committee on Quality Issues (CQI) (https://www. were considered; however, the CQI Guideline Writing
aacap.org/AACAP/Resources_for_Primary_Care/Practice_ Group exercised editorial authority as to whether the sug-
Parameters_and_Resource_Centers/Practice_Parameters. gested edits were included in the final document. Final
aspx).31 The CQI is charged by AACAP with the devel- approval of the guideline as an AACAP Official Action
opment of Clinical Practice Guidelines in accordance with rested with the AACAP Council.
standards promulgated by the Institute of Medicine
(IOM)32 and the Appraisal of Guidelines Research & ASSESSMENT OF ANXIETY
Evaluation (AGREE) Next Steps Consortium.33 Both Diagnostic evaluation is an essential prerequisite for the
standard sets emphasize rigor (critically appraised empirical treatment of an anxiety disorder. Specialized clinical edu-
evidence) and transparency (minimization of conflicts of cation, training, and experience are necessary to conduct a
interest and well-delineated guideline development process). diagnostic evaluation of a child or adolescent in accordance
CQI chairs are nominated by the AACAP president based with current psychiatric nomenclature (DSM-51). A diag-
upon their expertise and experience in the synthesis of nostic evaluation identifies the following: symptoms; syn-
psychiatric knowledge and their lack of relevant conflicts of dromal symptom combinations; symptom frequency,
interest. CQI members are nominated by CQI co-chairs to severity, onset, and duration; degree of associated distress
broadly represent AACAP members in geographic, gender, and functional impairment; developmental deviations; and
and professional practice type, duration and setting do- physical signs. Clinical expertise is required to differentiate
mains, and to have no relevant conflicts of interest. Pro- anxiety disorders from normal psychological processes
spective CQI members are reviewed and approved by the common to human experience.
AACAP president.
In this guideline, statements about the treatment of Identification
anxiety disorders are based upon empirical evidence derived At present, there is no empirically based (eg, U.S. Preventive
from a critical systematic review of the scientific literature Services Task Force) recommendation for universal
1108 www.jaacap.org Journal of the American Academy of Child & Adolescent Psychiatry
screening for anxiety disorders in children and adolescents. sets is the requirement for a specific frequency and duration
However, in primary care, school, or other child-serving of symptoms as well as clinically significant distress and
settings, freely available general socialemotional functional impairment, along with the caveat that alterna-
screening instruments (eg, Pediatric Symptom Checklist tive mental, medical, and substance-related explanations for
[https://www.massgeneral.org/psychiatry/treatments-and- the symptom presentation must have been ruled out before
services/pediatric-symptom-checklist/68]; Strengths and the diagnosis is applied.
Difficulties Questionnaire [http://www.sdqinfo.com69]) can In DSM-5,1 diagnostic criteria are provided for 11
be deployed systematically to standardize identification of anxiety disorders (one with 8 subcategories).a Although the
anxiety concerns. Early identification of an anxiety concern, boundaries between psychiatric disorders are now recog-
if confirmed as a problem upon follow-up assessment, can nized as porous, such that different disorders within and
facilitate early intervention, including guided self- across categories may share similar symptoms, risk factors,
management and focused intervention for subclinical and and neural substrates, diagnostic precision nonetheless is
mild presentations. key for understanding disorder course and prognosis and for
In the context of a psychiatric evaluation, symptoms of guiding empirically based treatment recommendations.
anxiety typically are identified through spontaneous youth According to DSM-5,1 separation anxiety is character-
or parent report (the presenting problem or chief ized by developmentally inappropriate, excessive worry or
complaint), during the clinician’s review of psychiatric distress associated with separation from a primary caregiver
symptoms, the conduct of the mental status examination, or or major attachment figure. Selective mutism is character-
through input from referral sources. However, because of ized by absence of speech in certain social situations despite
the variability inherent in nonsystematic methods of the presence of speech in other situations (usually at home).
identification, a more standardized approach may be Specific phobia is characterized by excessive fear or worry
useful. As one option, the American Psychiatric Association about a specific object or situation. Social anxiety is char-
(APA) developed the freely available parent- and self-rated acterized by excessive fear or worry about being negatively
Level 1 Cross-Cutting Symptom Measures (https://www. evaluated by others in social situations. Panic (ie, abrupt
psychiatry.org/psychiatrists/practice/dsm/educational-resources/ surge of intense fear or discomfort) is characterized by
assessment-measures70) to screen for multiple psychiatric recurrent unexpected panic attacks with physical and
disorders including anxiety. These instruments could be cognitive manifestations. Agoraphobia is characterized by
included in intake packets to systematically and efficiently excessive fear or worry about being in situations (eg, crowds,
gather information about presenting problems prior to the enclosed spaces) in which the individual may be unable to
evaluation. The parent and self-rated versions of the Level 1 escape or get help should panic-like or other overwhelming
Cross-Cutting measure have demonstrated good reliability or embarrassing symptoms occur. Generalized anxiety is
in the DSM-5 field trials conducted in pediatric clinical characterized by excessive, uncontrollable worries regarding
samples across the United States.71 numerous everyday situations or activities. Substance/
medication-induced anxiety and anxiety due to another
Evaluation medical condition are characterized by anxiety occurring in
Clinically significant anxiety (ie, an anxiety disorder) must the context of substance/medication use or a physical illness.
be distinguished from everyday worries and fears, which are When diagnostic criteria are not fully met for a given
common to the human experience and normative (even anxiety disorder or if a precise diagnosis is not possible due
when exaggerated) in specific developmental stages (eg, to limited information or other factors, DSM-5 includes
being startled and exposure to strangers in infants, separa- “other specified” and “unspecified” diagnoses to be applied
tion from caregiver in toddlers, supernatural creatures in in these circumstances. The “unspecified” diagnosis may be
preschoolers, physical well-being and natural disasters in the best diagnostic choice for nonbehavioral health
school-aged children, and social and existential concerns in a
DSM-5 Anxiety Disorders with International Classification of Diseases–
adolescents). In DSM-5,1 mental disorders are defined as “a 10 code: Separation Anxiety Disorder (ICD F93.0); Selective Mutism (ICD
syndrome characterized by clinically significant disturbance F94.0); Specific Phobia (Animal: ICD F40.218, Natural environment: ICD
F40.228, Fear of blood: ICD F40.230, Fear of injections and transfusions:
in an individual’s cognition, emotion regulation, or F40.231, Fear of other medical care: F40.232, Fear of injury: F40.233,
behavior that reflects a dysfunction in the psychological, Situational: F40.248, Other: F40.298); Social Anxiety Disorder (F40.10);
biological, or developmental processes underlying mental Panic Disorder (F41.0); Agoraphobia (F40.00); Generalized Anxiety Dis-
functioning.” By DSM convention, a mental disorder is order (F41.1); Substance/Medication-Induced Anxiety Disorder (see
substance-specific codes), Anxiety Disorder Due to Another Medical
diagnosed if all or a threshold of diagnostic criteria for the Condition (F06.4); Other Specified Anxiety Disorder (F41.8); and Un-
given disorder are met. Included in most diagnostic criteria specified Anxiety Disorder (F41.9).
clinicians, who may not possess detailed knowledge of so that the somatic symptoms are not falsely attributed to
DSM-5 criteria for specific anxiety disorders. adverse effects of medication treatment.
Medications that can cause anxiety include (but are not
Evaluation Structure. A diagnostic interview for anxiety
limited to) bronchodilators, nasal decongestants and other
includes the parent/guardian and patient, either separately
sympathomimetics, antihistamines, steroids, dietary sup-
or together or both as developmentally and clinically indi-
plements, stimulants, antidepressants, antipsychotics, and
cated. Interview of the patient requires a developmentally
withdrawal from benzodiazepines (particularly short-acting).
sensitive approach that may use multiple age-appropriate
Medication reconciliation is a routine part of an evaluation
assessment techniques (eg, direct and indirect questioning,
for a suspected anxiety disorder.
interactive and projective techniques, symptom rating
A wide array of licit and illicit substances can cause
scales, behavioral approach tests). Family assessment can
anxiety, including (but not limited to) marijuana, cocaine,
reveal environmental reinforcements for anxiety, and ob-
anabolic steroids, hallucinogens, phencyclidine, and with-
servations of parenting styles and behaviors can identify
drawal from nicotine, alcohol, and caffeine. Environmental
those that are potentially anxiogenic. Input from collateral
etiologies such as exposure to organophosphates and
sources (records, interviews, rating scales), including (as
ingestion of metals (eg, lead, arsenic) can also be considered.
applicable and with parent/guardianpatient consent) other
Although drug and toxin testing are not routine in the
family members, teachers, primary care and behavioral
evaluation of a suspected anxiety disorder, testing can be
health clinicians, and/or child agency workers, can add
considered if exposure is reported.
depth and breadth to diagnostic information. Because of the
Mental conditions that may include symptoms that are
multiple sources of information, a diagnostic evaluation of a
similar to those of anxiety disorders are ADHD (distracti-
child or adolescent may involve more than one session as
bility, restlessness), depression (distractibility, insomnia,
allowed by current diagnostic billing code (Current Proce-
somatic complaints), bipolar disorder (distractibility, rest-
dural Codes [CPT] 90791, 90792) specifications.
lessness, irritability, insomnia), obsessive-compulsive disor-
As lack of appropriate linguistic ability or interpreter
der (intrusive thoughts, avoidance, reassurance seeking),
support has been associated with misdiagnosis as well as
psychotic disorders (restlessness, agitation, social with-
adverse clinical outcomes,72 it is optimal to conduct the
drawal, distractibility), autism spectrum disorder (social
diagnostic evaluation in the language in which the child and
withdrawal, social skills deficits, distractibility), and learning
parents/guardians are proficient. If live interpreter services
disorders (worries about school performance).
are not available, telephonic or televideo interpreter services
may be an alternative.
Psychiatric Comorbidities. Anxiety disorders commonly
Differential Diagnosis. The primary goal of the history of co-occur with each other; other common comorbidities
1
present illness is to determine whether DSM-5 diagnostic include (but are not limited to) depression, ADHD, and
criteria for a specific anxiety disorder are met, and to rule behavior, bipolar, obsessive-compulsive, eating, learning,
out alternative explanations (“masqueraders”) for the language, and substance-related disorders. With selective
symptom presentation. In addition, characterization of mutism, developmental and communication disorders
previous anxiety presentations and response to previous frequently co-occur. Comorbidities may heighten distress
treatments will inform current treatment choice. and functional impairment and may worsen treatment
Medical conditions associated with anxiety include (but outcomes. Each comorbid disorder may require a separate
are not limited to) hyperthyroidism, caffeinism, migraine, treatment plan and may influence the selection of treatment
asthma, diabetes, chronic pain/illness, lead intoxication, for the anxiety disorder.
hypoglycemic episodes, hypoxia, pheochromocytoma, cen- Use of the Parent- and Self-Rated Level 1 Cross-
tral nervous system disorders, cardiac arrhythmias, cardiac Cutting Symptom Measures70 or screening questions
valvular disease, systemic lupus erythematosus, allergic re- embedded in structured interview guides can standardize
actions, and dysmenorrhea. Although laboratory testing is and enhance the efficiency of the psychiatric review of
not routine in the evaluation of a suspected anxiety disorder, symptoms to assess for psychiatric comorbidities. If screen
in collaboration with the child’s primary care practitioner, questions on these instruments are positively endorsed, the
testing (eg, glucose, thyroid function) can be completed if ensuing interview can ascertain whether full diagnostic
suggested by signs and symptoms of a medical condition. criteria are met for the given disorder. Each condition for
For anxious youths presenting with somatic symptoms, the which full diagnostic criteria are met are diagnosed as such,
nature and severity of those symptoms are noted at baseline unless DSM-5 hierarchical rules1 apply.
Medical Comorbidities. Children and adolescents with anxiety diagnosis, to characterize the nature and breadth of
anxiety disorders are more likely to present with a variety of specific symptoms, and to quantify pretreatment symptom
health problems, including headaches, asthma, gastrointes- severity as a baseline for tracking response to treatment
tinal disorders, and allergies. The anxiety and physical dis- over time. Moreover, in some situations, individual or
orders variously can be coincidental, in which the anxiety combinations of multi-informant symptom rating scales
that precedes or follows the physical disorder is related to may predict anxiety diagnoses as well as the ADIS struc-
factors other than the illness itself, or can be causal, in which tured interview, thereby reducing assessment burden.77
the anxiety contributes to or results from the physical Several anxiety rating scales with acceptable psychometric
illness. Examples of the latter include physical/physiological properties are freely available, both for the general
pathology secondary to anxiety symptoms, anxiety symp- construct of anxiety as well as for specific anxiety disorders;
toms secondary to physical pathology/physiology, and for example:
anxiety as a reaction to physical illness and/or treatment.
Whatever the presumed type of association, each disorder, Screen for Child Anxiety Related Emotional Disorders
whether physical or psychological, is separately assessed and (SCARED), parent and child versions https://www.
treated. pediatricbipolar.pitt.edu/resources/instruments78
Spence Children’s Anxiety Scale (SCAS), parent and child
Structured Interview Guides. Although the use of versions https://www.scaswebsite.com79
completely structured interview guides is infrequent in Preschool Anxiety Scale, parent version https://www.
nonresearch settings, such guides have been shown to scaswebsite.com79
substantially enhance the reliability of psychiatric diagnosis
Generalized Anxiety Disorder7 (GAD-7), teen/adult
over unstructured clinician interviews, which are vulnerable
version https://www.phqscreeners.com80
to a number of information collection biases.73 Structured
interview guides for children and adolescents have generally In addition, the APA offers the field-tested1 parent- and
similar, moderately acceptable psychometric properties; self-rated Level 2 Cross-Cutting Symptom Measures for
hence, the decision to use a structured interview as part of a Anxiety that explore anxiety endorsed on the Level 1
diagnostic evaluation will depend upon consideration of the Measure (“mild” or greater on any anxiety item) in greater
advantages (eg, enhanced diagnostic accuracy) and disad- depth, and the self-rated Disorder-Specific Severity Mea-
vantages (eg, time, cost, burden) specific to each situation sures for clinically diagnosed separation anxiety, specific
and setting. The use of computerized versions of interview phobia, social anxiety, agoraphobia, and generalized anxiety
guides could enable a psychiatric symptom review before disorders to track response to treatment over time (https://
the first appointment (ideally at home through a secure www.psychiatry.org/psychiatrists/practice/dsm/educational-
portal) as a structured, comprehensive first step in eluci- resources/assessment-measures70).
dating the differential diagnosis.74 There is poor to moderate agreement between parent
The proprietary Anxiety Disorders Interview Schedule and youth reports on structured interview guides and
(ADIS), considered in research settings to be a gold standard symptom rating scales.81,82 However, discrepancies between
for assessing childhood anxiety, addresses all DSM-IV anx- informants are to be expected, as they reveal each in-
iety disorders; in addition, screening sections for other formant’s unique view of the child’s anxiety symptoms,
psychiatric disorders are included to allow assessment of which are internal and may not be readily or accurately
comorbidities.75 A freely available option for structured discerned by others. Although the youth’s report is generally
assessment is the K-SADS PL (Present and Lifetime) DSM- considered to be paramount for internalizing disorders, 83,84
5 interview guide (https://www.pediatricbipolar.pitt.edu/ the simple rule of regarding a symptom as being present by
sites/default/files/KSADS_DSM_5_Supp3_AnxietyDO_ any informant’s report can be an acceptable resolution of
Final.pdf76), which includes sections assessing panic, discrepancies.
agoraphobia, separation anxiety, social anxiety, selective
Mental Status Examination. In the mental status exami-
mutism, specific phobia, and generalized anxiety disorders.
nation, signs of anxiety can include fastidious or disheveled
The K-SADS-PL DSM-5 also includes screening and
appearance, poor eye contact, poor engagement/uncooper-
follow-up questions for other disorder categories, which can
ativeness, shy demeanor, clinginess, tremor, fidgetiness/
facilitate efficient identification of potential anxiety mas-
restlessness, “nervous” habits, hypervigilance, poverty of or
queraders and comorbidities.
pressured speech, perseverative or ruminative thought pro-
Symptom Rating Scales. Although not diagnostic, stan- cesses, worry- or fear-laden thought content, distractibility,
dardized symptom rating scales can be useful to support an irritability/agitation, and poor insight and judgment.
Because these signs are nonspecific to anxiety (and may be and impulsivity, are assessed both at the time of evaluation
absent), they are largely adjunctive to other diagnostic and during treatment of an anxiety disorder, as these risks
information. have been associated both with anxiety and more rarely with
its treatment with antidepressant medications. Anxiety dis-
Clinical Formulation. Beyond diagnosis, the contextual (eg,
orders in general and separation anxiety in particular may
stressors, strengths, environmental supports, cultural/spiri-
suggest the need for exploration of exposure to traumatic
tual/gender/sexual orientation) and historical (eg, medical,
events. In the case of abuse or neglect, reporting to the state
developmental, educational, family, social) sections of the
child welfare authority is required. Gathering information
diagnostic evaluation guide the development of a clinical
from multiple sources and by varied culturally and devel-
formulation, which summarizes hypotheses regarding the
opmentally sensitive techniques may be needed in evalu-
biological, psychological, and social factors that may have
ating safety risks. Assessment culminates in two basic
predisposed, precipitated, or perpetuated the symptom
questions: Is the patient at current risk? Are the patient and
presentation.
family able to adhere to recommendations regarding su-
Key biological vulnerabilities for anxiety include family
pervision, safeguarding, and follow-up care? The answers to
history of an anxiety disorder signaling inherited vulnera-
these questions can lead to the appropriate level and in-
bilities in brain structure and function; acquired insult to
tensity of care. Psychiatric hospitalization is likely indicated
the developing brain; autonomic hyperreactivity; tempera-
when the youth actively voices intent to harm and in the
ment characterized by negative affectivity, behavioral inhi-
context of altered mental status (including severe anxiety/
bition, or sleeping/eating irregularity; and chronic medical
agitation), multiple previous self-harm attempts, previous
conditions. Hypothesized psychological vulnerabilities
unsuccessful treatment, and caregiver incapacity.
include those derived from attachment theory (insecure
attachment), cognitive-behavioral theory (maladaptive
Treatment Planning. Treatment planning derives from the
cognitive schemas, information-processing errors, negative
diagnoses and clinical formulation. High-quality treatment
self-evaluations, disconnects between feelings and behav-
plans are safe, timely, effective, efficient, feasible, equitable,
iors), psychodynamic theory (ego deficits, problems in
and child and family centered.86 A range of potentially
internalized object relations, unconscious conflicts), and
effective treatments and other interventions are explained in
mindfulness theory (instability of affect management). Key
accordance with the cognitive/linguistic/cultural level of the
social vulnerabilities include stressful/traumatic life events,
parents/guardians and patient, prioritized according to the
anxiogenic parenting behaviors (overprotection/overcontrol,
acuity, severity, distress, and impairment associated with
high rejection/criticism, modeling anxious thoughts), social
each diagnosed disorder. Reviewing the patient and parent/
skills deficits, peer rejection, inappropriate expectations for
guardian preferences regarding the treatment options pre-
achievement, lack of support/opportunities for competency
sented can increase the likelihood of engagement and
development, and sociodemographic/cultural discordance
adherence to the plan. Level of care decisions are informed
with prevailing norms (poor “fit” in a given environment).
by diagnosis, the current severity of symptoms, the presence
The biopsychosocial formulation can be organized to
of comorbid medical or psychiatric disorders, the assessment
reflect predisposing, precipitating, perpetuating, and pro-
of the child’s risk to self or others, the child’s prior illness
tective (ameliorating) factors (“4 P’s”) influencing the
course and complications, the child’s potential supports,
development of psychopathology.85 Predisposing factors are
and the treatment alliance between the clinician and the
areas of vulnerability that increase the risk for psychopa-
child and family.
thology and encompass primarily the biological factors of
In clinical practice, five components that generally are
the biopsychosocial formulation. Precipitating factors are
included in a discussion seeking to obtain informed consent
stressors or other contextual events that have a chronologic
for treatment are as follows87: 1) the diagnosis; 2) the nature
association with symptom onset. Perpetuating factors are
and purpose of the proposed treatment; 3) the attendant
any aspects of the patient, family, or community that serve
risks and benefits of the proposed treatment; 4) alternative
to perpetuate the symptoms. Protective (ameliorating) fac-
treatments and their risks and benefits; and 5) the risks and
tors include the patient’s own areas of strength as well as
benefits of declining treatment. Strategies for improving
strengths in the family and community. The cross-
parent/guardians’ and patients’ comprehension of risks and
organization of both biopsychosocial and 4P factors can
benefits can include providing written educational mate-
optimize the comprehensiveness of the treatment plan.
rials, multimedia presentations, decision-making work-
Safety. Safety risks, including but not limited to suicidal sheets, and standardized consent forms; asking for a “repeat
thoughts and behaviors, self-harm, risk-taking behaviors, back” of information provided; and engaging in back-and-
forth discussions until understanding is achieved. Docu- Errata from the original review were published in July
mentation of the informed consent process provides evi- 2018.36
dence that the patient and parent/guardian were adequately To be eligible for the AHRQ/Mayo review, studies
prepared to provide assent/consent for treatment. must have met all of the following criteria: 1) included
The incorporation of cultural and spiritual values, be- children and adolescents between 3 and 18 years old with a
liefs, and attitudes in treatment interventions can enhance confirmed diagnosis of panic, social anxiety, specific phobia
the child’s and family’s participation in treatment and (including school phobia), generalized anxiety, or separation
treatment effectiveness.72 Treatment recommendations can anxiety disorder who 2) received any psychotherapy or
draw from those proved to be effective in the minority pharmacotherapy, alone or combined; and 3) reported
population in question, and reflect ethnopharmacologic specified outcomes. Specified outcomes included the
factors (eg, pharmacogenomic, dietary, herbal) that may following: 1) primary anxiety symptoms from measures
influence the child’s response to medications or experience completed by the patient, parent, or clinician; 2) secondary
of adverse effects. anxiety outcomes such as coping, avoidance, or anxious
Successful treatment is a collaborative effort among all thoughts; 3) global function; 4) social function; 5) satis-
involved parties with well-defined roles and responsibilities, faction with treatment; 6) response to treatment; and 7)
including the clinician’s role in generating motivation in the remission of the disorder (see AHRQ/Mayo review for
child and parents/guardians to adhere to the treatment plan. measures used for each outcome category36). Both ran-
Inquiring about the parents’ understanding of the outcomes domized controlled trials (RCTs) and comparative obser-
of the assessment, addressing any questions or concerns, and vational studies were included for effectiveness outcomes;
discussing the logistics of treatment recommendations im- case reports or case series were also used to identify adverse
proves the chance that barriers to treatment are adequately events (AEs).
addressed. If treatment will be elsewhere, assisting the The key questions of the AHRQ/Mayo review were
family with the referral improves the likelihood of referral twofold: 1) what is the comparative effectiveness of the
completion. Parents/guardians who themselves struggle available treatmentsb for panic, social anxiety, specific
with anxiety can benefit from additional psychoeducation phobia (including school phobia), generalized anxiety, and
and support in fostering their child’s successful anxiety separation anxiety disorders? 2) What are the comparative
management; a referral for parental treatment may be potential harms regarding the available treatments for these
appropriate. disorders?
Feedback to the patient’s medical care team is
AHRQ/Mayo Systematic Review Rating Procedure. The
generally permissible with basic consent for treatment,
strength of evidence (SOE) for each measured outcome (eg,
although definitions of care team and regulations vary by
parent-rated anxiety symptoms) within each comparison
state. If parents/guardians specifically consent, feedback to
(eg, fluoxetine vs. CBT) across all studies included in the
child-serving systems with which the patient is involved
AHRQ/Mayo review was rated via a consensus process by
(medical, educational, juvenile justice, child welfare) can
the Mayo reviewers in accordance with the AHRQ Methods
facilitate coordination of care. Prompt, concise, and
Guide for Effectiveness and Comparative Effectiveness Re-
jargon-free feedback is most helpful; for example, feed-
views.88 Randomized controlled trials (RCTs) started with
back might include reiteration of the presenting problem/
high SOE; observational studies started with low SOE.
reason for referral, a brief description of the assessment
Initial SOE ratings based upon study type were then raised
process, the diagnoses given, and the treatments
or lowered in accordance with the SOE assessed across five
recommended.
additional domains: 1) risk of bias (impact on inference); 2)
precision (sample size, confidence intervals); 3) directness
TREATMENT OF ANXIETY
(relevance to patient); 4) consistency (degree of heteroge-
Development of Treatment Statements From the
AHRQ/Mayo Systematic Review
neity of findings); and 5) publication bias (nonpublication
The objective of the AHRQ/Mayo review34-36 was to b
Psychotherapy treatments: cognitive-behavioral therapy, parent-child
interaction therapy, problem-solving therapy, third-wave (mindfulness)
evaluate the effectiveness of psychotherapy and pharmacotherapy, psychodynamic psychotherapy, family therapy, attention
therapy for the treatment of specific child and adolescent modification, motivational interviewing, eye movement desensitization
anxiety disorders and to evaluate the safety concerns asso- reprocessing therapy (EMDR); pharmacologic treatments: sertraline,
ciated with these treatments. In August 2017, the AHRQ/ citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, venlafax-
ine, atomoxetine, reboxetine, duloxetine, alprazolam, chlordiazepoxide,
Mayo systematic review34 was made available in its entirety clonazepam, imipramine, clomipramine, mebicarum, buspirone, mirta-
on the Internet and as a synopsis in a pediatric journal.35 zapine, and nefazodone.
of study results). For RCTs, risk of bias was assessed using Evaluation (GRADE)91 convention by weighing the poten-
the Cochrane Risk of Bias tool89 (assessing random sequence tial benefits and harms of each treatment statement action
generation; allocation concealment; blinding of participants, and the level of confidence in that determination based
personnel, and outcome assessors; attrition bias; incomplete upon the underlying SOE.
outcome data; selective reporting). For observational studies,
A recommendation statement (denoted by the nu-
risk of bias was assessed using the NewcastleOttawa Scale90
meral 1) indicates confidence that the benefits of the
(assessing representativeness of the study population; selec-
action clearly outweigh the harms.
tion of cohorts; ascertainment of exposure and outcomes;
A suggestion statement (denoted by the numeral 2)
adequacy of follow-up; possible conflicts of interest). If
indicates greater uncertainty, in that the benefits of
insufficient evidence was available to determine SOE, that
the action are considered likely to outweigh the
finding was noted. The AHRQ/Mayo review process,
harms, but the balance is more difficult to judge.
including the flow chart, search strategy, study inclusion/
exclusion criteria, and individual study characteristics are The extent to which AHRQ/Mayo reviewderived
presented in detail in the published review.36 treatment statements were supported or refuted by more
recent meta-analyses37-43 was presented as additional evi-
CQI Treatment Statement Rating/Grading Procedure.
dence after each statement.
Based upon the findings from the AHRQ/Mayo review, the
Treatment statements underwent iterative blind voting
CQI Guideline Writing Group via a consensus process
developed treatment statements for each comparison for by the CQI Guideline Writing Group members until at
least majority consensus was achieved. If a voting outcome
which sufficient evidence was available. Each treatment
statement was assigned a numerical rating for SOE and a had not been unanimous, a dissenting opinion could have
been written to accompany the statement.
letter grade for the balance of benefits and harms as
described below. If insufficient evidence was available, no Applicability of Treatment Findings From the AHRQ/
treatment statement was developed; instead, the comparison Mayo Review. The treatment findings from the AHRQ/
was noted as in need of additional research. Mayo review36 were stated to be “likely widely applicable to
The treatment statement SOE ratings were determined a heterogeneous population of children and adolescents
by arraying the AHRQ/Mayo SOE ratings for each indi- with separation anxiety, generalized anxiety, social anxi-
vidual outcome across six key outcomes as available (ie, ety, panic, and specific phobia disorders, with minimal
child-rated anxiety symptoms; parent-rated anxiety psychiatric comorbidities, who are on average 8 to
symptoms; clinician-rated anxiety symptoms; response; 18 years old and have ready access to mental health
remission; global function). professionals who can provide CBT or have access to
medical professionals who are willing to prescribe SSRIs
If the preponderance of AHRQ/Mayo SOE ratings
or SNRIs.”
across the six key outcomes for a given comparison was
Of the disorders named above, because specific
high, the SOE rating for the corresponding treatment
phobia was not represented as the primary disorder in
statement was high (denoted by the letter A).
medication studies included in the AHRQ/Mayo review,
this disorder was not included in the AACAP medication
across the six key outcomes was moderate, the SOE
treatment statements. Although the AHRQ/Mayo find-
rating for the treatment statement was moderate
ings were said to apply to children and adolescents who
(denoted by the letter B).
were “on average” 8 to 18 years old, both medication and
therapy studies in the AHRQ/Mayo review included
across the six key outcomes was low, the SOE rating
children as young as 6 years old. Accordingly, the treat-
for the treatment statement was low (denoted by the
ment statements in this guideline extend downward to age
letter C).
6. Although the majority of studies in the AHRQ/Mayo
The treatment statement benefit/harm grades were review were conducted with populations that were pre-
determined by the CQI Guideline Writing Group via a dominantly of White ethnicity, there is no compelling
consensus process in accordance with the Grading of rationale for rendering the treatment statements inappli-
Recommendations Assessment, Development, and cable to minority populations.
Treatment Statementsc Additional Support. This recommendation was supported

by the findings from four meta-analyses published since
1. AACAP recommends (1C) that cognitive-behavioral the AHRQ/Mayo review.40-43 No meta-analyses or sys-
therapy (CBT) be offered to patients 6 to 18 years tematic reviews published since the AHRQ/Mayo review
old with social anxiety, generalized anxiety, separa- refuted this recommendation. One of the recent meta-
tion anxiety, specific phobia, or panic disorder. analyses43 suggested the possible superiority of group CBT
Benefits and Harms. Of the psychotherapy treatments over all other assessed psychotherapies and control
eligible for the AHRQ/Mayo review, only CBT had suffi- conditions.
cient outcome data for planned comparisons. A total of 60
Differences of Opinion. There were no differences of
RCTs and 3 nonrandomized comparative studies compared
opinion. The CQI Guideline Writing Group voted unan-
CBT to waitlist/no treatment, 29 RCTs and one non-
imously in favor of this recommendation.
randomized comparative study compared CBT to attention
control/treatment as usual, and 3 RCTs compared CBT to Quality Measurement Considerations. CBT should be
pill placebo (see AHRQ/Mayo review36 for study details). considered among treatments offered to patients 6 to 18
Overall, 6,978 patients were included (47.9% male; mean years old with social anxiety, generalized anxiety, separation
age 11.2 years, range 618 years). anxiety, specific phobia, or panic disorders.
Compared to inactive controls (waitlist/no treatment),
CBT improved primary anxiety symptoms (child, parent, Implementation. CBT is a diverse group of interventions
and clinician report), global function, and response to targeted at the three primary dimensions of anxiety:
treatment (all moderate SOE), and may have improved cognitive (eg, cognitive distortions about the likelihood of
remission of disorder (low SOE). However, there was harm), behavioral (eg, avoidance of potentially harmful
evidence of publication bias for studies using the waitlist/ situations), and physiologic (eg, autonomic arousal and
no treatment comparison, which lowered their SOE. CBT other somatic symptoms). Therapeutic interventions are
did not separate from waitlist/no treatment for satisfaction individually tailored to illustrate connections among worries
with care and secondary measures (both low SOE), and and fears, thoughts, and behaviors, and are strategically
there was insufficient evidence for social function. directed toward eliminating emotional and physical distress,
Compared to active controls (attention control/treat- changing maladaptive beliefs and attitudes, and alleviating
ment as usual), CBT improved only primary anxiety (child avoidance behavior. CBT typically is organized according to
report) (moderate SOE); CBT did not separate from an agenda that involves homework assignments for practice
attention control/treatment as usual for primary anxiety opportunities that reinforce skills and generalize them to the
(parent and clinician report), satisfaction, secondary mea- natural environment. Treatment is characterized by
sures, or remission of disorder (all low SOE). There was collaboration among the patient, family, and therapist, and,
insufficient evidence for global function, social function, in some cases, school personnel. The goal of structured
and response to treatment. CBT is to achieve meaningful symptomatic and functional
CBT did not separate from pill placebo for primary improvement within 12 to 20 sessions. Systematic assess-
anxiety (child report) or secondary measures (all low SOE). ment of treatment effectiveness using standardized symp-
There was insufficient evidence for primary anxiety (clini- tom rating scales can supplement the clinical interview, as
cian report), global function, or social function. use of these scales has been shown to optimize therapists’
Except as noted, CBT did not separate from pill pla- ability to accurately assess treatment response and
cebo, waitlist/no treatment, or attention control/treatment remission.92
as usual with respect to any short-term AEs (all low SOE). Specialized education, training, and experience are
Compared to pill placebo, CBT reduced dropouts (low necessary for the effective delivery of CBT. Specific CBT
SOE) and compared to waitlist/no treatment, CBT reduced elements for anxiety disorders can include the following:
dropouts due to AEs (low SOE). education about anxiety; behavioral goal setting with
c
contingent rewards; self-monitoring for connections be-
The treatment statements below are intended to apply to the named
anxiety disorders for which all diagnostic criteria are met, including the
tween worries/fears, thoughts, and behaviors; relaxation
requirements for duration, frequency/severity, and clinically significant techniques including deep breathing, progressive muscle
distress and/or functional impairment. Although the AHRQ/Mayo review relaxation, and guided imagery; cognitive restructuring that
findings were insufficient to recommend or suggest the sequence in challenges distortions such as catastrophizing, over-
which treatments should be offered, prudent sequencing may prioritize
CBT over SSRI for recent onset of milder, less distressing, and less generalization, negative prediction, and all-or-nothing
functionally impairing anxiety presentations. thinking; graduated exposure incorporating graded
exposure to a feared stimulus; and problem-solving and so- Except as noted, SSRIs as a class did not separate from
cial skills training relevant to anxiogenic situations. The pill placebo with respect to short-term AEs (all moderate to
number and combination of these elements vary according low SOE). Insufficient data precluded assessment of AEs
to the specific anxiety disorder being treated and the pa- related to suicidal ideation or behavior. Insufficient data also
tient’s clinical presentation. Graduated exposure, in which precluded assessment of AEs related to neurologic or oral
the patient creates a fear hierarchy that is then mastered in a (dry mouth) AEs.
stepwise manner, is the cornerstone of treatment for anxiety
Additional Support. This recommendation was supported
generated by a specific situation, such as in separation anx-
by the findings from three meta-analyses published since the
iety, specific phobias, and social anxiety. Developmentally
AHRQ/Mayo review.37-39 No meta-analyses or systematic
appropriate modifications of graduated exposure may
reviews published since the AHRQ/Mayo review refuted
include use of real-life desensitization (in vivo), emotive
this recommendation.
imagery (narrative stories), live modeling (demonstration of
nonfearful response), and contingency management (posi- Differences of Opinion. There were no differences of
tive reinforcement). Exposure is tailored to the individual opinion. The CQI Guideline Writing Group voted unan-
and calibrated in intensity in a manner similar to dosage imously in favor of this recommendation.
calibration in medication management.93
Quality Measurement Considerations. A medication from
Although CBT emphasizes cognitive, behavioral, and
the SSRI class should be considered among treatments
physiologic processes that lead to and maintain anxiety
offered to patients 6 to 18 years old with social anxiety,
symptoms, these processes are learned and function in a
generalized anxiety, separation anxiety, and panic disorders.
social context. As such, family-directed interventions that
improve parentchild relationships, strengthen family Implementation. Serotonergic function is believed to play a
problem-solving and communication skills, reduce parental key role in the ability of the brain to modulate fear, worry,
anxiety, and foster anxiety-reducing parenting skills often and stress as well as to facilitate cognitive processing of those
supplement individual treatment. In addition, school- emotions.94 The SSRI medication class is a group of
directed interventions that educate teachers about the stu- chemically and pharmacologically different compounds that
dent’s anxiety and how to foster effective problem-solving, inhibit the presynaptic reuptake of serotonin in the brain,
coping, and anxiety management strategies in the school thereby increasing availability of serotonin at the synaptic
setting can be part of the treatment plan. Specific plans for cleft. This blockade over time is believed to lead to a
anxiety management at school can be written into the stu- downregulation of inhibitory serotonin autoreceptors,
dent’s 504 plan or individualized education plan (eg, which eventually heightens the serotonergic neuronal firing
graduated school re-entry with contingent rewards for sep- rate, which in turn leads to increased serotonin release. This
aration anxiety; graduated practice opportunities for social multistep process is hypothesized to be related to the delay
anxiety). in onset of the SSRI treatment effect.
Medications from the SSRI class currently marketed in
2. AACAP recommends (1B) that selective serotonergic
the United States are citalopram, escitalopram, fluoxetine,
reuptake inhibitors (SSRIs) be offered to patients 6 to
fluvoxamine, paroxetine, sertraline, and vilazodone. In the
18 years old with social anxiety, generalized anxiety,
AHRQ/Mayo review, the SSRIs for which sufficient data
separation anxiety, or panic disorder.
were available for comparisons were fluoxetine, fluvoxamine,
Benefits and Harms. In the AHRQ/Mayo review (see
paroxetine, and sertraline. Although mechanisms of action
vary somewhat across SSRIs (eg, effects on other neuro-
AHRQ/Mayo review36 for study details), 13 RCTs
compared SSRIs to pill placebo. Overall, 1,708 patients transmitter receptors affecting degree of serotonin selectivity),
the primary mechanism was deemed in the AHRQ/Mayo
were included (54.1% male; mean age 11.6 years, range:
review to be sufficiently similar across individual medications
618 years).
to warrant extension of the findings to the medication class.
Compared to pill placebo, SSRIs as a class improved
Although there is substantial empirical support for the
primary anxiety symptoms (parent and clinician report),
response to treatment, and remission of disorder (all mod- effectiveness and safety of the SSRI class of medications for
the treatment of anxiety, no specific SSRIs have U.S. Food
erate SOE), as well as global function (high SOE). SSRIs
did not separate from pill placebo for primary anxiety and Drug Administration (FDA) approval for this indica-
tion. The choice of a specific SSRI is governed by consid-
symptoms (child report), secondary measures, or social
function (all low SOE). erations such as pharmacokinetics, pharmacodynamics,
tolerability, cost, insurance formularies, and unique risks to depressive disorders, may occur early in SSRI treatment,
leading to warnings or precautions. with dose increases, or with concomitant administration of
At present, there is no clear role for pharmacogenomic drugs that inhibit the metabolism of SSRIs. The potential
testing in medication selection, although this may change as for dose-related behavioral activation/agitation early in
additional evidence accumulates.95 treatment supports slow up-titration and close monitoring
Limited data are available on drug pharmacokinetics (particularly in younger children), and underscores the
and pharmacodynamics for SSRIs in young people. Most importance of educating parents/guardians and patients in
SSRIs (particularly fluoxetine because of its active metabo- advance about this potential side effect.
lite) have sufficiently long elimination half-lives to permit As with other antidepressants, there have been rare re-
single daily dosing. However, at low doses of sertraline96 ports of mania/hypomania that can be difficult to distin-
and at any dose of fluvoxamine, youths may require guish from behavioral activation. In general, behavioral
twice-daily dosing. activation may be more likely to occur early in treatment
The best-fitting model for SSRI response may be a (first month) or with dose increases, whereas mania/hypo-
logarithmic model demonstrating statistically (but not mania may appear later. Moreover, behavioral activation
clinically) significant improvement in anxiety symptoms usually improves quickly after SSRI dose decrease or
within 2 weeks of treatment initiation, clinically significant discontinuation, whereas mania may persist and require
improvement by week 6, and maximal improvement by more active pharmacological intervention. Sexual dysfunc-
week 12 or later.38 This pharmacodynamic profile supports tion (erectile dysfunction, delayed ejaculation, anorgasmia)
slow up-titration to avoid unintentionally exceeding the can occur with SSRIs in adolescents. Because seizures have
optimal medication dose. been observed in the context of SSRI use, SSRIs should be
As a group, the SSRIs are generally well tolerated by used cautiously in patients with a history of a seizure dis-
children and adolescents. Most adverse effects emerge order. Abnormal bleeding, especially with concomitant
within the first few weeks of treatment, and can include administration of aspirin or nonsteroidal anti-inflammatory
(but are not limited to) dry mouth, nausea, diarrhea, drugs, can occur with SSRIs; rare bleeding events include
heartburn, headache, somnolence, insomnia, dizziness, vivid ecchymosis, hematoma, epistaxis, petechiae, and
dreams, changes in appetite, weight loss or gain, fatigue, hemorrhage.
nervousness, tremor, bruxism, and diaphoresis. Potentially Serotonin syndrome, caused by elevated brain serotonin
serious adverse effects include (but are not limited to) sui- levels, can be triggered when serotonergic medications are
cidal thinking and behavior, behavioral activation/agitation, combined.99 Symptoms can arise within 24 to 48 hours
hypomania, mania, sexual dysfunction, seizures, abnormal after combining medications and are characterized by
bleeding, and serotonin syndrome. mental status changes (confusion, agitation, anxiety);
All of the SSRIs have a boxed warning for suicidal neuromuscular hyperactivity (tremors, clonus, hyperreflexia,
thinking and behavior through age 24 years. The pooled muscle rigidity); and autonomic hyperactivity (hyperten-
absolute rates for suicidal ideation across all antidepressant sion, tachycardia, arrhythmias, tachypnea, diaphoresis,
classes and all non-OCD anxiety indications have been re- shivering, vomiting, diarrhea). Advanced symptoms include
ported to be 1% for youths treated with an antidepressant fever, seizures, arrhythmias, and unconsciousness, which
and 0.2% for youths treated with a placebo.97 The pooled can lead to fatalities. Treatment is hospital based and in-
risk difference has been reported to be 0.7% (95% confi- cludes discontinuation of all serotonergic agents and sup-
dence interval 0.4% to 2%; p ¼ .21), yielding a number portive care with continuous cardiac monitoring.
needed to harm (NNH) of 143 (compared to a number Monoamine oxidase inhibitors (MAOIs), including phe-
needed to treat [to achieve response] of 3).97 Despite the nelzine, isocarboxazid, moclobemide, isoniazid, and line-
low apparent risk, close monitoring for suicidality is rec- zolid play a role in most cases of serotonin syndrome and
ommended by the FDA, especially in the first months of should be avoided in combination with any other seroto-
treatment and following dosage adjustments. Although the nergic drug, including another MAOI. Moreover, caution
margin of safety of SSRIs in overdose is greater than for should be exercised when combining two or more non-
other antidepressants, deaths have been reported following MAOI serotonergic drugs, including antidepressants (eg,
very large ingestions. SSRIs, SNRIs, TCAs, atypical antidepressants); opioids and
Behavioral activation/agitation98 (eg, motor or mental other pain medications (eg, tramadol, meperidine, metha-
restlessness, insomnia, impulsiveness, talkativeness, dis- done, fentanyl); stimulants (eg, amphetamine and possibly
inhibited behavior, aggression), more common in younger methylphenidate classes); cough/cold/allergy medications
children than adolescents and in anxiety disorders compared (eg, dextromethorphan, chlorpheniramine); other over-the-
counter products (eg, St. John’s wort, L-tryptophan, diet to the clinical interview, along with reported and
pills); and illicit drugs (eg, ecstasy, methamphetamine, observed adverse events. If a concerning adverse effect is
cocaine, LSD). Caution entails starting the second non- reported or observed that could reasonably be linked to
MAOI serotonergic drug at a low dose, increasing the the medication, in general the dose of medication would
dose slowly, and monitoring for symptoms, especially in the be reduced, and if the concerning adverse effect persists,
first 24 to 48 hours after dosage changes. the medication would be discontinued. For all SSRIs,
Each SSRI has special prescribing considerations. Par- medical monitoring can include height and weight; no
oxetine, fluvoxamine, and sertraline have been associated specific laboratory tests are recommended. The optimal
with discontinuation syndrome100 (see below for syndrome duration of pharmacologic treatment of anxiety disorders
description). As noted below, fluvoxamine may have greater for continued symptom remission is unclear, but a
potential for drugdrug interactions. Citalopram may cause generally accepted approach would be to continue an
QT prolongation associated with Torsade de Pointes, ven- effective, tolerated dose for approximately 12 months
tricular tachycardia, and sudden death at daily doses after remission, monitoring for several months after
exceeding 40 mg/d and should be avoided in patients with discontinuation for re-emergence of symptoms. Discon-
long QT syndrome. Paroxetine has been associated with tinuation generally should occur during a relatively stress-
increased risk of suicidal thinking or behavior compared to free period. Some youths with severe and chronic anxiety
other SSRIs. presentations may require lengthier medication treatment.
SSRIs vary in their potential for drugdrug in- Determinants of nonadherence to medication regi-
teractions.101 Concomitant administration of any of the mens are multidetermined, including social/economic,
SSRIs with any of the monoamine oxidase inhibitors health system, illness, patient, and treatment factors.102
(MAOIs) is contraindicated because of increased risk of Although evidence is mixed, some effective strategies
serotonin syndrome. SSRIs (especially citalopram) also may include behavioral (motivational), educational (informa-
interact with drugs that prolong the QT interval; fluoxetine, tion pamphlets), integrated care (care coordination), self-
paroxetine, and sertraline may interact with drugs metabo- management (illness management skills), risk communi-
lized by CYP2D6, and fluvoxamine may interact with drugs cation (harm avoidance), and packaging/daily reminder
metabolized by CYP1A2, CYP2C19, CYP2C9, CYP3A4, (physical or technological) approaches.102 In children and
and CYP2D6. Citalopram/escitalopram may have the least adolescents, parental oversight of medication regimens is
effect on CYP450 isoenzymes compared with other SSRIs of paramount importance.
and as such may have a lower propensity for drug A discontinuation syndrome characterized variously by
interactions. dizziness, fatigue, lethargy, general malaise, myalgias, chills,
Medical education, training, and experience are headaches, nausea, vomiting, diarrhea, insomnia, imbal-
necessary to safely and effectively prescribe antidepressant ance, vertigo, sensory disturbances, paresthesias, anxiety,
medications. A conservative medication trial for mild to irritability, and agitation has been reported following missed
moderate anxiety presentations may entail increasing the doses or acute discontinuation of shorter-acting SSRIs,
dose as tolerated (if adherence is confirmed) within the notably paroxetine but also (to a lesser extent) fluvoxamine
therapeutic dosage range in the smallest available in- and sertraline.103 Accordingly, these medications warrant
crements at approximately 1- to 2-week intervals when close adherence to the prescribed regimen and a slow
prescribing shorter half-life SSRIs (eg, sertraline, cit- discontinuation taper. In contrast, fluoxetine, likely because
alopram, escitalopram) to approximately 3- to 4-week of the long half-life of its active metabolite, is unlikely to be
intervals when prescribing longer half-life SSRIs (eg, associated with discontinuation syndrome and has not been
fluoxetine) until the benefit-to-harm ratio is optimized associated with withdrawal symptoms when doses are
and remission is achieved. Faster up-titration may be missed.
indicated as tolerated for more severe anxiety pre- There is no definitive empirical guidance for switching
sentations; however, it is not clear that dose of medica- from one SSRI to another.104 Although the most conser-
tion is related to magnitude of response, and higher doses vative approach would entail tapering and discontinuing the
or blood concentrations can be associated with more first SSRI before adding the second (with a washout interval
adverse effects.38 Because an initial adverse effect of SSRIs if the first SSRI is fluoxetine), this approach entails the risk
can be anxiety or agitation, it may be advisable to start of exacerbation of the original symptoms, or discontinua-
with a subtherapeutic dose as a “test” dose. Systematic tion symptoms if the first SSRI (other than fluoxetine) is
assessment of treatment response using standardized stopped abruptly. Cross-tapering may avoid these outcomes,
symptom rating scales can be considered as a supplement but should be closely monitored.
3. AACAP suggests (2C) that combination treatment definitive evidence for the superiority of combination
(CBT and an SSRI) could be offered preferentially treatment over monotreatment (therapy or medication
over CBT alone or an SSRI alone to patients 6 to 18 alone). Largely derived from the findings from one of the
years old with social anxiety, generalized anxiety, studies (the Child-Adolescent Anxiety Multimodal Study
separation anxiety, or panic disorder. [CAMS]),105 expert consensus generally supports the pri-
oritization of combination treatment over monotreatment.
Benefits and Harms. In the AHRQ/Mayo review, two
In CAMS,106 youths who received combination treatment
RCTs compared combination treatment (CBT and an
had significantly higher rates of remission compared to
SSRI) to either treatment alone (see AHRQ/Mayo review36
monotreatment with SSRI or CBT or with placebo treat-
for study details). These 2 studies included 550 patients
ment at week 12 and week 24. In clinical practice, com-
(52.6% male; mean age 12.2 years, range 717 years).
bination treatment may be favored if there is a need for
Compared to CBT alone and to sertraline alone,
acute symptom reduction in a severe, functionally impairing
combination CBT plus sertraline improved primary anxiety
disorder or a partial response to monotreatment.
(clinician report), global function, response to treatment,
Combination treatment typically involves concurrent
and remission of disorder (all moderate SOE).
administration of psychotherapy (CBT in the AHRQ/
Combination CBT plus fluoxetine did not separate
Mayo-included studies) and medication (an SSRI in the
from CBT alone for global function, secondary measures, or
AHRQ/Mayo-included studies). Optimally, combination
response to treatment (all low SOE) and may have reduced
treatment would be delivered in the same facility to enhance
remission of disorder compared to CBT alone (low SOE).
convenience for the patient and family as well as commu-
Except as noted, combination CBT plus sertraline did
nication between treatment providers.
not differ from CBT alone with respect to short-term AEs
Naturalistic follow-up of the CAMS study (Child/
including suicidal ideation or behavior (all low SOE).
Adolescent Anxiety Multimodal Extended Long-term Study
Compared to CBT alone, combination CBT plus sertraline
[CAMELS])107 failed to demonstrate long-term mainte-
increased AEs related to behavior activation (moderate
nance of the initial superiority of combination over mon-
SOE) and increased any AEs and AEs related to sleep (both
otreatment. However, a strong predictor of long-term
low SOE).
outcome was initial response to treatment, which, in the
Except as noted, combination CBT plus sertraline did
CAMS study, was significantly superior in the combination
not differ from sertraline alone with respect to short-term
treatment compared to the monotreatment arms.106 This
AEs (all low SOE). Compared to sertraline alone, combi-
finding may suggest the importance of delivering what may
nation CBT plus sertraline increased AEs related to behavior
be the most potent treatment (combination) early in the
activation and reduced AEs due to fatigue/somnolence
treatment course.
(both moderate SOE). Insufficient evidence precluded
assessment of AEs related to suicidal ideation or behavior. 4. AACAP suggests (2C) that serotonin norepinephrine
Compared to CBT alone, combination CBT plus reuptake inhibitors (SNRIs) could be offered to pa-
fluoxetine did not differ with respect to dropouts tients 6 to 18 years old with social anxiety, general-
(low SOE). ized anxiety, separation anxiety, or panic disorder.
Additional Support. This suggestion was not supported or
Benefits and Harms. In the AHRQ/Mayo review, 4 RCTs
refuted by the findings from any meta-analyses or systematic
compared SNRIs to pill placebo (see AHRQ/Mayo review36
reviews published since the AHRQ/Mayo review.
for study details). These studies included 911 patients
Differences of Opinion. There were no differences of (63.4% male; mean age 12.4 years, range 617 years).
opinion. The CQI Guideline Writing Group voted unan- Compared to pill placebo, SNRIs as a class improved
imously in favor of this suggestion. primary anxiety symptoms (clinician report) (high SOE).
SNRIs did not separate from pill placebo for primary anx-
Quality Measurement Considerations. Combination
iety (parent report) or global function (both low SOE).
treatment (CBT plus an SSRI) can be considered among
Insufficient data precluded assessment of primary anxiety
treatments offered to patients 6 to 18 years old with social
(child report).
anxiety, generalized anxiety, separation anxiety, and panic
Except as noted, SNRIs as a class did not separate from
disorders.
pill placebo with respect to short-term AEs including sui-
Implementation. Because there were only two studies with cidal ideation or behavior (all moderate to low SOE).
conflicting results, the AHRQ/Mayo review did not find Compared to pill placebo, SNRIs were associated with
increased fatigue/somnolence (moderate SOE). Insufficient pharmacodynamics, tolerability, cost, insurance formularies,
data precluded assessment of AEs related to infections. and unique risks leading to warnings or precautions. At
present, there is no clear role for pharmacogenomic testing
Additional Support. This suggestion was supported by the
in medication choice, although this may change as evidence
findings from three meta-analyses published since the
accumulates.
AHRQ/Mayo review.37-39 There were no meta-analyses or
Limited data are available on drug pharmacokinetics
systematic reviews published since the AHRQ/Mayo review
and pharmacodynamics of SNRIs for young people. Ven-
that refuted this suggestion.
lafaxine extended release, desvenlafaxine, and duloxetine
Differences of Opinion. There were no differences of have sufficiently long elimination half-lives to permit single
opinion. The CQI Guideline Writing Group voted unan- daily dosing. Because of its short elimination half-life,
imously in favor of this suggestion. venlafaxine immediate release may require twice- or
thrice-daily dosing.
Quality Measurement Considerations. A medication from
Adverse effects of SNRIs can include (but are not
the SNRI class can be considered among treatments offered
limited to) diaphoresis, dry mouth, abdominal discomfort,
to patients 6 to 18 years old with social anxiety, generalized
nausea, vomiting, diarrhea, dizziness, headache, tremor,
anxiety, separation anxiety, and panic disorders.
insomnia, somnolence, decreased appetite, and weight loss.
Implementation. The SNRI medication class is a group of The SNRIs also have been associated with sustained clinical
chemically and pharmacologically different compounds that hypertension, increased blood pressure, and increased pulse.
inhibit the presynaptic reuptake of both norepinephrine and As described above for SSRIs, uncommon but poten-
serotonin in the brain.94 Stress responses including alert- tially serious adverse effects across the SNRI class include
ness, arousal, attentiveness, and vigilance are believed to be suicidal thinking and behavior (through age 24 years),
modulated by noradrenergic neurons. Although associated behavioral activation/agitation, hypomania, mania, sexual
with the stress response (“fight or flight”) and the generation dysfunction, seizures, abnormal bleeding, and serotonin
of fear and anxiety, paradoxically noradrenergic medications syndrome. In addition, individual SNRI medications have
have been shown empirically to be effective in the treatment also been associated with distinctive, potentially serious
of anxiety disorders, likely because of complex interactions (albeit rare) adverse effects.
with other neurotransmitters including serotonin. Venlafaxine may be associated with greater suicide risk
Medications from the SNRI class currently marketed in than the other SNRIs,108,109 and both venlafaxine and
the United States are venlafaxine, desvenlafaxine, dulox- desvenlafaxine have been associated with overdose fatalities.
etine, and levomilnacipran. In the AHRQ/Mayo review, the Venlafaxine also has been associated with discontinuation
SNRIs for which sufficient data were available for com- symptoms.
parisons were venlafaxine and duloxetine. Atomoxetine (a Duloxetine has been associated with hepatic failure
selective norepinephrine reuptake inhibitor) also was presenting as abdominal pain, hepatomegaly, and elevation
included in the AHRQ/Mayo review under the SNRI class; of transaminase levels. Cholestatic jaundice also has been
however, at present, the effectiveness of atomoxetine for the reported. Duloxetine should be discontinued and not
treatment of anxiety as the primary disorder has not been restarted in patients who develop jaundice or other evidence
established, and as such atomoxetine is not further of clinically significant liver dysfunction. Severe skin re-
addressed in this guideline. actions, including erythema multiforme and
Although mechanisms of action vary somewhat across StevensJohnson syndrome, can occur with duloxetine;
SNRIs (eg, effects on other neurotransmitter receptors accordingly, duloxetine should be discontinued and not
affecting degree of serotonin and norepinephrine selec- restarted at the first appearance of blisters, peeling rash,
tivity), the primary mechanism was deemed in the AHRQ/ mucosal erosions, or other signs of hypersensitivity.
Mayo review to be sufficiently similar across individual SNRIs vary in their potential for drugdrug in-
medications to warrant extension of the findings to the teractions. Concomitant administration of any of the SNRIs
medication class. and any of the MAOIs is contraindicated because of
Duloxetine is the only SNRI to have an FDA indication increased risk of serotonin syndrome. Duloxetine may
for the treatment of any anxiety disorder (specifically, interact with drugs metabolized by CYP1A2 and CYP2D6.
generalized anxiety disorder in children and adolescents Compared to SSRIs, venlafaxine may have the least effect on
717 years old). However, the choice of medication for the CYP450 system.110
anxiety within the SNRI class may also be governed by Medical education, training, and experience are neces-
other considerations such as pharmacokinetics, sary to safely and effectively prescribe antidepressant
medications. The recommendations for an adequate SNRI Relatively small body of evidence, especially for medica-
trial are the same as those delineated above for SSRIs. For all tion studies
SNRIs, medical monitoring should include height, weight, Brief follow-up of most studies
pulse, and blood pressure; no specific laboratory tests are Use of different symptom rating scales across studies to
recommended. assess improvement
As with SSRIs, a discontinuation syndrome has been Lacking, sparse, or unstratified descriptions of potentially
reported103 following missed doses or acute discontinuation mediating and moderating variables (eg, intervention
of SNRIs. Accordingly, SNRIs also warrant a slow discon- components, participant demographics, comorbidities,
tinuation taper. symptom severity)
Poor representation across studies of both very young
Areas for Additional Treatment Research children and young adults
For many important domains of treatment for anxiety Poor representation across studies of multiracial youths
(listed below), the AHRQ/Mayo review yielded insufficient Paucity or lack of medication studies addressing selective
information to draw conclusions about the benefits or mutism, specific phobias, panic, or agoraphobia as the
harms of the treatment. As such, treatment statements for primary disorder
these domains are not offered. Research is urgently needed Variable methods for reporting treatment-emergent
to support additional treatment statements in these domains adverse events and serious adverse events
for future guidelines. Insufficient data to assess risk of suicidal behavior
Circumstances suggesting preferential use of SSRIs The limitations of the Assessment and Implementation
or CBTd sections of this guideline reflect the derivation of the
Preferential sequencing of SSRIs and CBTe narrative from a single time-limited review by the CQI
Treatment effect modifiers (eg, child/family characteris- Guideline Writing Group of published expert opinion and
tics, treatment setting, disorder severity, comorbidities)f consensus. When expert opinions differed, judgment was
Use of non-CBT psychotherapiesg exercised by the CQI Guideline Writing Group to select
Use of benzodiazepinesh among equally supported opinions. Although differences in
Long-term safety risks of pharmacologic treatmenti professional judgment are possible, any differences are
Effectiveness of psychosocial and pharmacologic treat- deemed unlikely to affect the overall conclusions of the
ments in underserved populations and minoritiesj guideline.
LIMITATIONS CONCLUSIONS
The limitations of the Treatment section of this guideline Congruent with previous national and international guide-
reflect the derivation of the treatment statements from the lines,62-65 in this guideline both cognitive-behavioral
findings of a single, time-limited, critical systematic review therapy (CBT) and selective serotonin reuptake inhibitor
of the literature by the AHRQ-contracted Mayo Clinic (SSRI) medication have considerable empirical support as
Evidence-based Practice Center in which reviewers’ judg- safe and effective short-term treatments for anxiety in
ment played a role in rating the strength of the empirical children and adolescents. Serotonin norepinephrine reup-
evidence. Despite the rigor and transparency of the sys- take inhibitor (SNRI) medication has some empirical sup-
tematic review process as delineated in the AHRQ/Mayo port as an additional treatment option. CBT may be
review,36 differences in professional judgment are possible. considered to be the first-line treatment for anxiety in
However, any differences are deemed unlikely to affect the children and adolescents, particularly for mild to moderate
overall conclusions of the guideline. Other limitations of the presentations, with SSRI (and possibly SNRI) medication
AHRQ/Mayo review are as follows: an alternative treatment consideration, particularly for more
severe presentations or when quality CBT is unavailable.
d
AHRQ/Mayo review: equivocal head-to-head comparisons of SSRI Combination treatment (CBT and SSRI) may be a more
vs CBT
e
AHRQ/Mayo review: no data
effective short-term treatment for anxiety in children and
f
AHRQ/Mayo review: equivocal subgroup analyses adolescents than either treatment alone. Because effective
g
AHRQ/Mayo review: excluded from analyses due to heterogeneity of treatment outcomes are predicated in part upon accuracy of
therapies the diagnosis, depth of the clinical formulation, and breadth
h
AHRQ/Mayo review: one poor quality trial of BZP versus placebo
i
AHRQ/Mayo review: no data of the treatment plan, comprehensive, evidence-based
j
AHRQ/Mayo review: no data assessment may enhance evidence-based treatment.
In the context of a protracted severe shortage of child Formal analysis: Walter, Bukstein, Abright, Keable, Ramtekkar, Ripperger-
and adolescenttrained behavioral health specialists, Suhler, Rockhill
Investigation: Walter, Bukstein, Abright, Keable, Ramtekkar, Ripperger-Suhler,
research demonstrating convenient, efficient, cost-effective, Rockhill
and user-friendly delivery mechanisms for safe and effec- Methodology: Walter, Bukstein, Abright, Keable, Ramtekkar, Ripperger-Suhler,
Rockhill
tive treatments for child and adolescent anxiety disorders is Project administration: Walter
an urgent priority. Pharmacotherapeutic task-sharing with Supervision: Walter
Writing e original draft: Walter, Bukstein, Abright, Keable, Ramtekkar,
pediatric practitioners, particularly for moderate anxiety Ripperger-Suhler, Rockhill
presentations, can greatly expand access to safe and effective Writing e review and editing: Walter, Bukstein, Abright, Keable, Ramtekkar,
Ripperger-Suhler, Rockhill
care while conserving child and adolescent psychiatrists for Karen Ferguson and Ron Szabat, JD, LLM served as the AACAP staff liaisons
the management of more severe and complex presentations. for the CQI.
ORCIDs:
The comparative effectiveness of anxiety treatments, delin- Heather Walter: 0000-0002-1594-6638
eation of mediators and moderators of effective anxiety Oscar Bukstein: 0000-0002-6324-1392
A. Reese Abright: 0000-0002-3467-3807
treatments, long-term effects of SSRI and SNRI use in Helene Keable: 0000-0002-7358-1227
children and adolescents, and additional evaluation of the Ujjwal Ramtekkar: 0000-0001-5988-7994
Jane Ripperger-Suhler: 0000-0001-6149-4022
degree of suicide risk associated with SSRIs and SNRIs, Carol Rockhill: 0000-0001-5799-9706
remain other key research needs. The authors acknowledge the following topic experts for their contributions to
this guideline: Boris Birmaher, MD, John Piacentini, PhD, Moira Rynn, MD,
The AACAP Clinical Practice Guidelines critically assess and synthesize scien- Jeffrey Strawn, MD, John Walkup, MD, V. Robin Weersing, PhD.
tific and clinical information as an educational service to AACAP members and The guideline underwent peer review from February 1, 2019, to March 11, 2020;
other interested parties. The treatment statements in the guidelines are based peer reviewers were as follows: Christopher Bellonci, MD, John Diamond, MD,
upon information available on the date of publication of the corresponding Laurence Greenhill, MD, Roma Vasa, MD (AACAP Committee on Quality Is-
AHRQ/Mayo systematic review. The guidelines are not continually updated sues); Debra Koss, MD, Karen Pierce, MD, Laura Willing, MD (AACAP Advocacy
and may not reflect the most recent evidence. The guidelines should not be Committee); Cathryn A. Galanter, MD, Alice Mao, MD (AACAP Consumer Is-
considered to be a statement of the standard of care nor exclusive of all proper sues Committee); Andrew Harper, MD, Lindsay Moskowitz, MD (AACAP
treatments or methods of care. The guidelines do not account for individual Continuing Medical Education Committee); Adelaide Robb, MD, Tim Wilens,
variation among patients. As such, it is not possible to draw conclusions about MD, Mina Dulcan, MD (AACAP Psychopharmacology Committee); Daniel
the effects of not implementing a particular recommendation, either in general Dickstein, MD, Manpreet Singh, MD (AACAP Research Committee); Debra
or for a specific patient. The ultimate decision regarding a particular assess- Koss, MD, Marian Swope, MD (Executive Committee, AACAP Assembly of
ment, clinical procedure, or treatment plan must be made by the clinician in Regional Organizations); Victor Fornari, MD, Richard Martini, MD (Presidents,
light of the psychiatric evaluation, other clinical data, the patient’s and family’s American Association of Directors of Child and Adolescent Psychiatry); AACAP
personal preferences and values, and the diagnostic and treatment options Members; AACAP Council.
available. Use of these guidelines is voluntary. AACAP provides the guidelines
This Clinical Practice Guideline was approved by AACAP Council on March
on an “as is” basis, and makes no warranty, expressed or implied, regarding
11, 2020.
them. AACAP assumes no responsibility for any injury or damage to persons or
property arising out of or related to any use of the guidelines or for any errors This Clinical Practice Guideline is available at www.aacap.org.
or omissions.
During the preparation of this guideline, none of the authors had any financial
The primary intended audience for the AACAP Clinical Practice Guidelines is conflicts of interest to disclose.
child and adolescent psychiatrists; however, the information presented also
Correspondence to the AACAP Communications Department, 3615 Wisconsin
could be useful for other medical or behavioral health clinicians.
Avenue NW, Washington, DC 20016.
Author Contributions:
Conceptualization: Walter, Bukstein, Abright, Keable, Ramtekkar, Ripperger-
0890-8567/$36.00/ª2020 Published by Elsevier Inc. on behalf of the American
Suhler, Rockhill
Academy of Child and Adolescent Psychiatry.
Data curation: Walter, Bukstein, Abright, Keable, Ramtekkar, Ripperger-Suhler,
Rockhill https://doi.org/10.1016/j.jaac.2020.05.005
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Clinical Practice Guideline for the Assessment and

Treatment Statementsc Additional Support. This recommendation was supported

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