This presentation will familiarize prescribers with signs, symptoms of anxiety disorders in children and teens, examine pivotal studies comparing the impacts of medication vs. psychotherapy in treatment of kids with anxiety, compare the benefits and risks of FDA-approved and “off-label” medications used to treat pediatric anxiety disorders and explore recent data comparing advantages, disadvantages of specific SSRIs used to treat anxiety in children, teens

1. Evaluation and Treatment
of Anxiety Disorders in
Children and Teens
Stephen Grcevich, MD
Family Center by the Falls, Chagrin Falls OH
Clinical Associate Professor of Psychiatry,
NEOMED
Stark MHAR “Lunch and Learn” Series
December 2021

2. Learning objectives:
• Familiarize prescribers with signs, symptoms of
anxiety disorders in children and teens
• Examine pivotal studies comparing the impacts
of medication vs. psychotherapy in treatment of
kids with anxiety
• Compare the benefits and risks of FDA-
approved and “off-label” medications used to
treat pediatric anxiety disorders
• Explore recent data comparing advantages,
disadvantages of specific SSRIs used to treat
anxiety in children, teens

3. Some
worries are
normal and
age-
appropriate
in children:
• Infants: Fear of loud noises, fear of being
startled
• Toddlers/Young Children: Fear of imaginary
creatures, fear of the dark, animals, strangers
• School-age children: Worry about injury, natural
events (storms), death
• Older children, teens: Fears related to school
performance, social competence, health issues
J Am Acad Child Adolesc Psychiatry 2007;46(2) 267-83.

4. How kids with anxiety disorders
differ from their peers
• They misinterpret threat, danger
• They think too much…to the point that
academic performance, family functioning,
friendships, extracurricular activities are
compromised…rumination, perseveration,
indecisiveness, perfectionism
We treat when anxiety interferes with
daily functioning

5. Neuroimaging findings

6. Source: NIMH

7. Source: CDC

8. Cumulative incidence and age
of onset of anxiety disorders
Beesdo K, Pine D, Lieb R; et al. Arch Gen Psychiatry. 2010;67(1):47-57

9. Epidemiology of Anxiety Disorders
• 8% of teens ages 13-18 have anxiety disorders
• Average age of onset - 6
• 2:1 sex ratio, girls>boys
• Phobias, panic disorder, agoraphobia, separation anxiety
• Severity = persistence
• Kids with one disorder often develop other disorders
• Increased risk of depression, substance abuse
• Fewer than one in five affected teens ever receive
anxiety-specific treatment
http://www.nimh.nih.gov/health/publications/anxiety-disorders-in-children-and-adolescents/index.shtml
J Am Acad Child Adolesc Psychiatry, 2007;46(2):267-283

10. Specific Anxiety Disorders in
Children, Adolescents:
Note: Kids may meet criteria for different anxiety as they progress
through developmental stages
• Separation Anxiety Disorder
• Specific Phobia
• Generalized Anxiety Disorder
• Social Anxiety Disorder
• Panic Disorder
• Selective Mutism
• OCD spectrum disorders categorized separately in DSM-5,
but closely related
J Am Acad Child Adolesc Psychiatry, 2007;46(2):267-283

11. Warning signs of
significant anxiety in
children and teens:
• “What if” questions
• Avoidance
• Excessive need for
reassurance
• Somatic complaints
• Sleep disturbances
Increased sleep latency
• Inattention, poor
concentration
• Perfectionism
• Excessive school absence
• Easily distressed
• Lying

12. Differential diagnosis of anxiety
disorders
• ADHD
• PTSD
• Asperger’s Disorder
• Learning Disabilities
• Depression
• Psychotic Disorders
• Medication-induced anxiety symptoms

13. Comorbidity and
pediatric anxiety
disorders
• Nearly three in four children
with depression also have
anxiety
• One in three children with
anxiety also have disruptive
behavior disorders
• Approximately one in three
children with anxiety also
have depression.
Centers for Disease Control and Prevention. (2020). Data
and statistics on children’s mental health

14. Social Anxiety
Disorder
• Marked fear or anxiety in one or
more social situations with exposure
to possible scrutiny
• Age of onset 8-15, prevalence 7%
• Onset often follows a stressful or
humiliating experience (being
bullied, embarrassed by a teacher
or coach)
• May manifest through…
• Difficulty speaking in class
• Talking on the phone
• Self-advocacy in school
• Applying for a job
• Dating

15. Specific Phobia
• Marked fear/anxiety about a specific
object or situation (flying, heights, natural
events, animals/insects, injections, blood)
• Manifested in children by crying, tantrums,
freezing, clinging
• Age of onset typically between 7 and 11
• Prevalence 5% in children, 16% in teens
• Risk factors include…
• Overprotective parents
• Traumatic experiences with feared
object
• Parental loss, separation
• Physical, sexual abuse

16. Separation Anxiety
Disorder
• Fear, anxiety around actual or anticipated separation
from attachment figures
• Prevalence 4% in children, 1.6% in teens
• Younger children often manifest difficulties…
• Attending school (too much time in nurse’s
office)
• Sleeping in their own bed
• Tolerating psychiatric interview without
caregiver
• With babysitters
• Older children may experience…
• Difficulty with sleepovers, overnight camp
• Fear of harm coming to themselves, parents
• Difficulty transitioning between homes in
divorce

17. Panic Disorder
• Recurrent, unexpected surges of intense fear or
discomfort, reaching a peak within minutes,
accompanied by persistent worry, avoidance.
• Prevalence in adolescents 2-3%, 2:1 female
• Median age of onset=20
• Frequently comorbid with other anxiety disorders,
depression
• Agoraphobia is now a separate condition, peaks in
late adolescence, early adulthood
• Adolescent prevalence 1.7%

18. Generalized
Anxiety
Disorder
• Excessive anxiety/worry, difficult to control,
occurring more days than not for at least six
months, accompanied by restlessness, fatigue,
concentration difficulties, irritability, muscle tension
or sleep disturbance.
• Prevalence 0.9% in adolescence
• Focus of worry…
• School performance
• Athletic performance
• Friendships

19. Selective Mutism
• Failure to speak in social situations when
speech is expected
• May not be an issue until entering school
• Rare in clinical settings, common in school (1%
prevalence)
• Characterized by…
• Excessive shyness
• Clingy
• Social isolation
• Tantrums
• Irritability

20. Obsessive-
Compulsive Disorder
• Presence of obsessions OR
compulsions - or both
• Tics are more common in boys with
childhood-onset of symptoms.
• 25% of cases present by age 14,
• Onset prior to age 10 in 25% of males
• Males more commonly affected in
childhood
• Children have more “harm”
obsessions, adolescents more
sexual, religious obsessions

21. OCD Related Disorders
• Body Dysmorphic Disorder
• Hoarding Disorder
• Trichotillomania
• Excoriation Disorder
• Represents a group of conditions that may be
treated in a similar fashion

22. Screening for
anxiety in
children, teens
• Essential to
identify multiple
informants
• Must differentiate
age-appropriate
fears, appropriate
fears for living
situation.
• Rating scales
• SCARED (parent,
child)
• Y-BOCS for
childhood OCD

23. Treatment of anxiety disorders
in children and adolescents
• Cognitive-behavioral therapy (with
modifications for specific anxiety disorders)
• SSRIs, other medications
• Parent-child, family interventions
• Classroom-based accommodations,
interventions
Evidence-based interventions in YELLOW
J Am Acad Child Adolesc Psychiatry, 2007; 46(2):267-283

24. CAMS (Child-
Adolescent Anxiety
Multimodal Study):
• NIMH-funded, RCT
comparing placebo,
sertraline, CBT and
combination (CBT +
sertraline) for separation
anxiety disorder, social
anxiety disorder, GAD
• Children, ages 7-17, N=488
• CBT: 14 sessions, using
“Coping Cat” curriculum
• Sertraline: started at 25
mg/day, increased by fixed-
flexible titration (mean
dose:133 mg/day)
Walkup JT et al, N Engl J Med, 2008;359:2753-2766

25. CAMS Study Results
• Response rates: COMB:
80.7%, CBT: 59.7%, SER:
54.9%, PBO: 23.7%
• COMB>CBT=SER>PBO
• Effect Sizes: COMB: 0.86,
SER: 0.45, CBT: 0.31
• No adverse effects>PBO in
medication groups
• Beneficial effects of COMB vs.
SER evident after week 8
0
10
20
30
40
50
60
70
80
90
%Responders
%Responders
Walkup JT et al, N Engl J Med, 2008;359:2753-2766

26. CAMS: Impact of severity on
treatment response
• Patients with severe
anxiety were most
likely to need
combination
treatment to achieve
remission
• Patients with
moderate anxiety
were as likely to
achieve remission
on medication alone
vs. combination
therapy
Taylor JH et al. Journal of Clinical Child and Adolescent Psychology. 2018. 47:2, 266-281.

27. Moderators of treatment
response in CAMS study
• Factors associated with less favorable
outcomes:
• More severe and impairing anxiety
• Greater caregiver strain
• Principal diagnosis of social phobia
• Kids with social anxiety disorder experienced
slightly better outcomes from SRT vs. CBT
• Patients with GAD showed somewhat better
outcomes with CBT vs. SRT
• Greatest added benefit to COMB treatment in
patients with separation anxiety disorder
Compton SN et al. J Consult Clin Psychol 2014;82(2):212-224

28. Pediatric OCD
Treatment (POTS)
Study
• 12 week, RCT comparing
placebo, CBT alone,
sertraline, CBT + sertraline,
N=112, ages 7-17
• Six week, “fixed flexible”
medication titration – mean
maximum dose 170 mg in
sertraline group, 133 mg in
combined group
• 14 sessions offered in CBT,
combination groups
• Three sites (Duke, Penn,
Brown)
March JS et al. JAMA 2004;292(16):1969-1976

29. Change in CY-YBOCS scores
by treatment group
March JS et al. JAMA 2004;292(16):1969-1976

30. POTS: Remission Rates
0
10
20
30
40
50
60
COMB CBT SER PBO
Remission %
Remission %
March JS et al. JAMA 2004;292(16):1969-1976

31. POTS results
• All active treatments superior to placebo, well-
tolerated
• Combined treatment superior to CBT alone,
sertraline alone
• CBT alone = sertraline alone
• For clinical remission (CYBOCS = 10 or under)
• Combination
• Equal to CBT alone
• Superior to sertraline, PBO
• CBT alone
• Equal to sertraline alone
• Superior to PBO
• Sertraline alone = PBO
March JS et al. JAMA 2004;292(16):1969-1976

32. Moderators of response
in POTS study
• Greater improvement associated
with…
• Lower OCD severity
• Less OCD-related functional
impairment
• Fewer comorbid externalizing
conditions
• Greater insight
• Patients with a first degree relative
with OCD had a six-fold reduction in
effect size of CBT monotherapy
• CBT is of little benefit in youth with a
family history of OCD unless given
in combination with an SSRI

33. FDA-approved
medications for
pediatric anxiety
disorders, OCD
• Sertraline (OCD) – ages 6 and up
• Duloxetine (GAD) – ages 7 and up
• Fluoxetine (OCD) – ages 7 and up
• Fluvoxamine (OCD) – ages 8 and up
• Clomipramine (OCD) – ages 10 and
up
Other treatments with RCTs, no FDA
indication
• Paroxetine (OCD, Social Anxiety)
• Venlafaxine (Social Anxiety)
• Atomoxetine (GAD, SAD, Social Anxiety +
ADHD)
• Imipramine (school phobia)

34. Pediatric Anxiety
Meta-Analysis:
Efficacy
• Superior to placebo:
• SSRIs
• SNRIs
• Alpha – 2 agonists
• SSRIs superior to
SNRIs
• Most effective to least
effective:
• SSRIs
• SNRIs
• Alpha- 2 agonists
Dobson ET et al, J Clin Psychiatry
2019;80(1):17r12064

35. SSRI vs. SNRI
efficacy in pediatric
anxiety disorders
• SSRIs produced
significantly
greater response
than SNRIs by
week two and
every other point
out to Week 12
• Bottom line: SSRIs
produce more
rapid and greater
improvement in
pediatric anxiety
compared to
SNRIs.
Strawn S et al. J Am Acad Child Adolesc Psychiatry 2018;57(4):235-244

36. Effect of
antidepressant
dose, class in
pediatric anxiety
disorders
• Improvement occurred
more rapidly on high-
dose SSRIs vs. low-
dose SSRIs
• No significant
differences in magnitude
of treatment response
between high and low-
dose SSRIs.
• Higher doses don’t
impact long-term
response but may result
in more behavioral
activation.
Strawn S et al. J Am Acad Child Adolesc Psychiatry 2018;57(4):235-244

37. Time course of response to
sertraline in pediatric anxiety

38. SSRI treatment durability:
fluvoxamine

39. Serotonin transporter
binding:
• 80% serotonin
transporter
saturation is
typically
achieved on 20
mg fluoxetine
dose
• Higher doses
may produce
little additional
benefit with
significantly
more adverse
effects

40. Pediatric Anxiety Meta-Analysis:
Efficacy
• Three treatments superior to placebo: fluvoxamine, sertraline,
fluoxetine
• Sertraline superior to buspirone
• Most effective treatment – fluvoxamine (clomipramine least
effective)
• Paroxetine superior to clomipramine, alprazolam, buspirone,
atomoxetine, venlafaxine, fluoxetine, duloxetine
Dobson ET et al, J Clin Psychiatry 2019;80(1):17r12064

42. How well do SSRIs work in
kids with anxiety, OCD?
SSRI Use Effect Size
Anxiety 0.69
OCD 0.48
Depression 0.25
Bridge JA et al, JAMA 2007; 297(15):1683-1696

43. Pediatric Anxiety Meta-Analysis:
Tolerability
• No significant differences in all-cause discontinuation
• SSRIs most tolerable class, TCAs least tolerable
• Discontinuation due to adverse events…
• SNRIs most tolerable, Alpha-2 agonists least tolerable
• SNRIs superior tolerability to alpha-2 agonists, benzodiazepines, 5HT1a
agonists, SSRIs
• TCAs superior to alpha-2 agonists, benzodiazepines
• SSRIs superior to alpha-2 agonists
Dobson ET et al, J Clin Psychiatry 2019;80(1):17r12064

44. SSRI-related weight gain
• Citalopram, escitalopram most strongly associated with increase in all body
composition measures, including visceral fat mass
• Associations with fluoxetine were somewhat weaker.
• Sertraline was not different from no SSRI treatment
Calarge CA, Mills JA, Janz KF, et al. Pediatrics. 2017;140(1):e20163943

45. SSRI side effects:
• Nausea
• Weight gain
• Behavioral activation/disinhibition
• Restlessness
• Potential for withdrawal
• Vivid dreams
• Increased clotting time
• Fatigue
• Sexual side effects

46. SSRI Withdrawal

47. SSRI Half-lives

48. Behavioral
Activation
• Characterized by:
• Disinhibition
• Impulsivity
• Irritability
• Hyperactivity
• Insomnia
• Restlessness

50. Managing activation
• Consider comorbidity (ADHD, bipolar disorder,
trauma)
• Decrease dose of SSRI
• Consider “microdosing” with liquids
• Change to a different SSRI
• Introducing CBT (or switching to
psychotherapy-only approach)
• Watch for increased risk of suicidal behavior

51. Side effect
management:
Future role
for
genotyping?
Strawn JR et al. J Child Adolesc Psychopharmacology 2019;29(5),340-347.

52. Benefits of twice-
daily dosing with
sertraline
From Strawn JR et al. J Child Adolesc
Psychopharmacology 2019;29(5),340-347.

53. Pediatric
Anxiety
Meta-Analysis:
Treatment –
emergent
suicidality
• SNRIs most tolerable class, TCAs least
• Treatment-emergent suicidality
significantly greater with paroxetine vs.
sertraline, duloxetine, placebo
• Higher rates seen with guanfacine,
clonazepam, duloxetine, venlafaxine and
placebo vs. sertraline
• Sertraline most tolerable active treatment,
paroxetine least tolerable
Dobson ET et al, J Clin Psychiatry 2019;80(1):17r12064

54. Predictors of Suicidal Events
Grcevich SJ et al. Presented at American Academy of Child and Adolescent Psychiatry, October 2009

55. Do risks and benefits vary by the condition
being treated?
(Number Needed to Harm)
0
50
100
150
200
250
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNH

56. Risk/Benefit Ratio of SSRIs by
condition treated
0
5
10
15
20
25
30
35
40
Depression Anxiety OCD
Risks and benefits of antidepressant therapy
Harm=New onset suicidal thinking, behavior
NNT Risk/Benefit

58. Buspirone in Pediatric Anxiety
Disorders
• Two RCTs – one fixed dose, one flexible
dose
• No significant difference in response
between active drug vs. placebo
• Well-tolerated – lightheadedness only AE
more frequent in active drug vs placebo
• Studies weren’t adequately powered to
detect possibility of a small effect size
(Cohen’s d<0.15)
Strawn S et al. J Child Adolesc Psychopharmacol 2018;28(1):2-9

59. Guanfacine XR
in pediatric
anxiety
• Proof of concept study,
RCT, N=83
• Doses 1-6 mg/day,
max dose
0.12/mg/kg/day
• Well-tolerated
• No significant
difference on PARS,
SCARED
• Significantly more
patients were “much”
or “very much”
improved on CGI (54.2
vs. 31.6%)
Strawn S et al. J Child Adolesc
Psychopharmacol 2017;27(1):29-37

60. Benzodiazepines in pediatric
anxiety
• No FDA indication for use
• Controlled studies largely include RCTs with
very short-acting agents (midazolam) for
anxiety associated with medical procedures
• Three negative RCTs in pediatric anxiety
• Short-term adjunct to SSRIs for rapid reduction
of severe anxiety symptoms (school refusal,
panic attacks)
• Contraindicated in youth with substance use
disorders
J Am Acad Child Adolesc Psychiatry 2007; 46(2):267-283.

62. Treatment of
Pediatric OCD

63. Metanalysis of medication
trials for pediatric OCD:
• Comparative effects of SSRIs (paroxetine,
fluoxetine, fluvoxamine, sertraline) and
clomipramine
• All medications superior to placebo
• No difference in efficacy between SSRIs
• SSRI effect sizes are modest
• Clomipramine superior to…
• Fluoxetine (p<0.03)
• Paroxetine (p=0.003)
• Fluvoxamine (p=0.001)
• Sertraline (p<0.001)
Geller DA et al. Am J Psychiatry 2003;160:1919-1928

64. Clomipramine (Anafranil)
• Most effective medication for OCD
• TCA – need to monitor EKG for QT prolongation
• CMI is serotonergic, active metabolite (DMCI) is
noradrenergic, converted through first pass
metabolism in liver
• Want CMI/DMCI ratio >1
• Adding low dose fluvoxamine inhibits P-450
mediated conversion of CMI to DMCI
• Intravenous CMI used in refractory cases
(bypasses first pass metabolism)
Walkup J. Presented at 2017 AACAP Annual Meeting, Washington DC

65. Pediatric OCD Treatment
Algorithm
Bloch MH, Starch AE. J Am Acad Child Adolesc Psychiatry 2015;54(4):251-262

66. For how long
should we treat?
• Discontinuation trials are non-existent
• Consider after patient has had minimal
symptoms for 6-12 months
• Reasonable in kids with problematic
side effects
• Taper slowly to minimize risk of OCD
relapse from discontinuation symptoms
• Taper during time of relatively low stress
• CBT booster visits helpful in patients
who received combination therapy
Bloch MH, Starch AE. J Am Acad Child Adolesc Psychiatry
2015;54(4):251-262

67. Factors associated with treatment
outcomes in pediatric OCD
• SSRIs less effective in patients with comorbid tics
• Patients with prominent hoarding at least 1/3 less
likely to respond to medication, behavioral therapy
• Diminished response to CBT, medication in the 30-
40% of patients with low insight
• Family accommodation, involvement associated
with poorer outcomes
• A small group of patients (NNT=17) may respond
better to SSRIs at doses > upper limits of FDA
approval
Bloch MH, Starch AE. J Am Acad Child Adolesc Psychiatry 2015;54(4):251-262

68. OCD Treatment Summary
• Most clinicians will start with an SSRI
• Consider augmenting with a second SSRI in
partial responders
• Clomipramine in patients who have failed two
or more SSRI trials, +/- low dose fluvoxamine
• Augmentation with risperidone as treatment of
last resort
• Remission is considered CY-YBOCS of 10 or
less or >35% improvement on standardized
outcome measure

69. Conclusions:
• Anxiety is one of the two most common mental
disorders among children and teens in the U.S.
• Children with anxiety disorders often become
symptomatic during their grade school years
• Most children and teens with anxiety never
receive any evidence-based treatment
• Cognitive-Behavioral therapy (CBT) and
medication are effective treatments for kids
with anxiety…best response generally when
CBT, medication used together

70. Contact
information
• drgrcevich@fcbtf.com
• sgrcevich@neomed.edu
• Twitter: @drgrcevich
• LinkedIn:https://www.linkedin.com/in/
stephen-grcevich-md/