DEPRESSION
AND
ANXIETY 28 : 76–87 (2011)
Review
ADVANCES IN PHARMACOTHERAPY FOR PEDIATRIC
ANXIETY DISORDERS
Moira Rynn, M.D.,1 Anthony Puliafico, Ph.D.,2 Charlotte Heleniak, B.A.,2 Pranav Rikhi,3 Kareem Ghalib, M.D.,2
and Hilary Vidair, Ph.D.2
Pediatric anxiety disorders are prevalent, chronic, and often lead to significant
impaired functioning that impacts both short- and long-term outcomes for
children and adolescents. Treatment options include pharmacotherapy and
psychosocial interventions. This presentation will review treatment advances
specifically for pharmacotherapy. Current research supports serotonin reuptake
inhibitors as the medication class to be the first-line treatment option for
pediatric anxiety disorders. Available evidence for the efficacy of other classes of
medications will be reviewed, along with the available approaches to manage
partial responders and nonresponders. The risks and benefits of pharmacotherapy
will also be reviewed. In addition, recent research has shown the potential
promise of novel agents that act upon other neural systems implicated
in the development of pediatric anxiety disorders. Novel compounds that affect
the glutamate system will be discussed. Depression and Anxiety 28:76–87,
r 2011 Wiley-Liss, Inc.
2011.
Key words: pharmacotherapy; pediatric; anxiety
A
INTRODUCTION
nxiety disorders are the most common type of
psychiatric disorders diagnosed in children,[1] with a
prevalence rate of between 6 and 20%.[2] The average
age of onset for this type of disorder is 11 years, and
age ranges from 6 to 21 years.[3] Of course, it is
completely normal for children to experience some
degree of worry; however, those children who are
diagnosed with an anxiety disorder can experience
great distress and impairment in academic, social, and
family functioning. The rates for child and adolescent
obsessive–compulsive disorder (OCD) are between 0.5
and 2%,[4] whereas rates of childhood posttraumatic
stress disorder (PTSD) may be as high as 24–34.5% in
urban areas.[5,6] However, it should be noted that these
rates vary depending on population, methodology, and
type of traumatic event.[7]
Anxiety disorders can be chronic and are highly
comorbid with additional anxiety disorders,[8] major
depression,[9] and disruptive behavior disorders.[10]
Childhood anxiety disorders often lead to difficulties
in adolescence and adulthood, such as anxiety and
depressive disorders,[11] substance abuse and dependence,[12] and suicidal behavior.[13] As a clinician or
researcher focused on child and adolescent anxiety, it is
r 2011 Wiley-Liss, Inc.
important to know how to recognize clinical presentations of anxiety and what evidence-based treatment
options are available.
PHARMACOLOGICAL STUDIES IN
PEDIATRIC ANXIETY DISORDERS
Presently, the most effective known treatments for
childhood-onset anxiety disorders are cognitive–behavioral
1
New York State Psychiatric Institute, New York, New York
Columbia University, Child Psychiatry Department, New York,
New York
3
Hunter College, Educational Psychology Department, New York,
New York
2
Correspondence to: Moira Rynn, New York State Psychiatric
Institute, 1051 Riverside Drive, Box 74, New York, NY 10032.
E-mail: [email protected]
The authors report they have no financial relationships within the
past 3 years to disclose.
Received for publication 15 October 2010; Accepted 19 October
2010
DOI 10.1002/da.20769
Published online in Wiley Online Library (wileyonlinelibrary.com).
Review: Advances in Pharmacotherapy for Pediatric Anxiety
therapy (CBT), behavior therapy (BT), and antidepressant medications, specifically the serotonin reuptake inhibitors (SSRIs). The following discussion will
focus on randomized clinical trials (RCTs), which
investigated the efficacy of treating child and adolescent suffering from a variety of anxiety disorders with
medication or medication in combination with CBT.
See Table 1 for study details and medications.
GENERALIZED ANXIETY DISORDER
Lana, age 12, has worried about many different things
over the past year, including what will happen if her mother
gets sick, if her parents cannot afford their house, or if she
fails a math test. She has trouble concentrating and becomes
easily fatigued. Usually, if she starts worrying about one
issue, she starts thinking of others, and often seeks
reassurance from her mother. When her mother gets annoyed
with her questioning, Lana gets very upset. Her mother
describes her ‘‘as my little old lady.’’
Rynn et al.[14] were the first to examine the effects of
medication for children and adolescents with a primary
diagnosis of generalized anxiety disorder (GAD) with
or without separation anxiety disorder.[14] The 9-week
study involved 22 children, ages 5–17 years. The
efficacy of sertraline was assessed. Sertraline was found
to be superior to placebo for reducing anxiety
symptoms (see Table 1). In another study of GAD,
Rynn et al.[15] compared venlafaxine ER (a serotonin–norepinephrine reuptake inhibitor) to placebo.[15]
Pooled analysis indicated that 69% of participants
responded to medication versus 48% to placebo (see
Table 1).[15] The dose was titrated based on weight and
response. Adverse events, such as asthenia, pain,
anorexia, and somnolence, were experienced at least
twice as often by the medication group versus the
placebo group. Additionally, significant changes in
weight, height, heart rate, blood pressure, and cholesterol level were observed in children in the venlfaxine
ER group.
SOCIAL PHOBIA
Nick, age 14, has always had difficulty making friends. At
school, he sits by himself at the lunch table. Over the years,
his teachers have described him as a pleasant, well-behaved
child, a little on the shy side. He wants to make new friends,
but is not sure how to start conversations with his peers.
When he speaks to someone, he starts thinking, ‘‘I know they
won’t like me’’ and worries about what he looks and sounds
like. He knows this is irrational, but describes not feeling
comfortable in his ‘‘own skin,’’ and is constantly concerned
about embarrassing himself in front of his peers and teachers.
Medication studies. Wagner et al.[16] found that
treatment of pediatric social phobia with paroxetine led
to higher response rates than placebo (78% with
medication group versus 38% with placebo) (see
Table 1).[16] Adverse events (e.g. insomnia, decreased
appetite, and vomiting) were experienced at least twice
as often in the medication group than the placebo
77
group. Upon discontinuation of paroxetine, nausea,
dizziness, and vomiting were experienced twice as
much by the medication group than the placebo group.
In another RCT, March et al. examined the efficacy
of venlafaxine ER in the treatment of social phobia.[17]
The study found that participants receiving venlafaxine
had a greater reduction in their social anxiety
symptoms compared to placebo (response rates in the
two groups were 56 versus 37%, respectively) (see
Table 1). Both groups reported mild-to-moderate
adverse events. Approximately 6% of participants on
medication experienced significant weight loss.
Comparative trial. Beidel et al. compared Social
Effectiveness Therapy for Children (SET-C), fluoxetine, and a pill placebo in children and adolescents
with social phobia.[18] Both the SET-C and the
fluoxetine group performed better than the placebo
group (see Table 2). However, the SET-C group had
significantly higher response rates as compared to
fluoxetine and placebo (79 versus 36 versus 6%,
respectively). The diagnostic remission rates were 53
versus 21 versus 3%, respectively. Treatment with
SET-C was found to be superior to placebo for
increasing social skills and social competence. There
were no severe adverse events reported. However, some
participants on fluoxetine experienced side effects, e.g.
diarrhea. Treatment gains were maintained upon
follow-up after 1 year.
POSTTRAUMATIC STRESS DISORDER (PTSD)
Eliana, age 16, was sexually abused last year by a friend of
her older brother. At first, she told herself it was no big deal,
but six months ago she started having vivid flashbacks of this
incident and thoughts that maybe it was her fault that it
happened. She also has nightmares about him running after
her and has difficulty falling asleep. She feels irritable, has
difficulty concentrating, and has been avoiding going out with
her friends because even a boy’s smile reminds her of the abuse.
In a study conducted by Cohen et al. the effects
of trauma-focused CBT (tf-CBT) combined with
sertraline were compared with tf-CBT plus placebo.[19]
Participants consisted of 24 children, ages 10–17 years,
who were experiencing PTSD (92%) or Posttraumatic
Stress Syndrome. Both groups experienced significant
reduction in PTSD symptoms, and no significant
difference was found between treatment groups (see
Table 2).
OBSESSIVE–COMPULSIVE DISORDER
Dylan, age 9, has been having trouble finishing his
homework because he feels the need to start over if he makes
one mistake. His father tried to convince him to just erase,
but he feels really nervous unless he starts all over. Lately,
when he goes to bed, he cannot fall asleep unless he arranges
all of his action figures four times in a specific order and
checks that the windows in his room are locked. Once that is
done, he silently repeats, ‘‘You got everything done’’ to help
him fall asleep.
Depression and Anxiety
Depression and Anxiety
OCD
Multiple Anxiety Diagnoses
Generalized Anxiety Disorder
(GAD)
Social phobia (SOP)
School refusal, over anxious
disorder, and separation
anxiety disorders
N 5 103, ages 7–17, 13 weeks
N 5 120, ages 8–17, 10 weeks
N 5 43, ages 8–17, 8 weeks acute,
then 16 weeks maint
N 5 193, ages 8–17 with additional
comorbid diagnoses. After 16
weeks Paroxetine
N 5 203, ages 7–17, 10 weeks
Geller et al.[23]
Riddle et al.[25]
Liebowitz et al.[24]
Geller et al.[26]
Geller et al.[27]
N 5 187, ages 6–17, 12 weeks
March et al.[21]
N 5 320, ages 6–17, 8 weeks
Rynn et al.[15]
N 5 60, ages 10–17, 8 weeks
N 5 22, ages 5–17, 9 weeks
Rynn et al.[14]
Deveaugh-Geiss et al.[20]
N 5 293, ages 8–17, 16 weeks
March et al.[17]
N 5 74, ages 7–17, 12 weeks
N 5 322, ages 8–17, 16 weeks
Wagner et al.[16]
Birmaher et al.[93]
N 5 24, ages 7–18, 8 weeks
Bernstein et al.[37]
N 5 128, ages 6–17, 8 weeks
N 5 21, ages 6–15, 6 weeks
Klein et al.[33]
Rupp Anxiety Study Group:
Walkup et al.[40]
N 5 51, ages 9–14, 12 weeks
Berney et al.[29]
Design
N 5 35, ages 6–14, 6 weeks
Study
Gittelman-Klein and
Klein[31]
TABLE 1. Acute treatment studies
Paroxetine (10–50 mg/day) 4
placebo
Fluoxetine (20–60 mg/day)4placebo
Fluvoxamine (50–200 mg/day)4
placebo
Fluoxetine (20–80 mg/day)
5 placebo at 8 weeks,4
placebo at 16 weeks
Paroxetine (10–60 mg/day)
5 placebo
Clomipramine (25–200 mg/day)4
placebo
Sertraline (Max 200 mg/day)4
placebo
Fluoxetine (20 mg/day)4placebo
(P 5.003)
Venlafaxine (37.5–225 mg/day)4
placebo
Fluvoxamine (50–300 mg/day)4
placebo (Po.001)
Clomipramine (40–75 mg/day)
5 placebo
Imipramine (75–275 mg/day)
5 placebo
Alprazolam (0.75–4 mg/Day)
5 Imipramine (50–175 mg/day)
5 placebo
Paroxetine (10–50 mg/day)
4placebo (Po.001)
Venlafaxine Er (37.5–225 mg/day)
4placebo (P 5.001)
Srt (25–50 mg/day)4placebo
Imipramine (100–200 mg/day)
4placebo (Po.05),
Results
N/A
N/A
N/A
In 6-month open-label phase, 94%
of fluvoxamine responders
maintained improvement (RuppASG, 2002)
At 1 year follow up, Fluoxetine
Responders maintained
improvement (Clark et al., 2005)
Improvement maintained After 1
year extension of Clomipramine
Improvement maintained after 1 year
extension of sertraline (Cook
et al.[22])
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
Follow-up
78
Rynn et al.
At 36 weeks, superiority of combined
treatment is maintained (ABCT, 2009)
N/A
CBT1Sertraline (25–200 mg/day)4
Sertraline 5 CBT4Placebo (Po.05)
CBT1Sertraline (25–200 mg/day)4
CBT 5 Sertraline4Placebo
Asbahr et al.
N 5 40, ages 9–17, 12 weeks
(2005)
Pots Team: March N 5 112, ages 7–17, 12 weeks
et al. (2004)
Multiple Anxiety Child anxiety
N 5 488, ages 7–17, 12 weeks
Disorders
multimodal
study (CAMS),
Walkup et al.[40]
Beidel et al.[18]
Social Phobia
OCD
Bernstein et al.[38] N 5 63, ages 12–18, 8 weeks
School refusal
N 5 122, ages 7–17, 12 weeks
Trauma focused (Tf)-CBT1Sertraline
N/A
(50–200 mg/day) 5 Tf-CBT1Placebo,
CBT1Imipramine (Mean 182.3 mg/day)4 Many met diagnostic criteria at 1 year
CBT1Placebo (Po.001)
(Bernstein et al.[39])
64.1% met criteria for anxiety disorder
33.3% Met Criteria For depressive disorder
Social effectiveness therapy for children
Maintained at 1 year
(SET-c)4Fluoxetine (10–40 mg/day)4
placebo (Po.001),
Group CBT 5 Sertraline (25–200 mg/day) gCBT4sertraline at 9 months
N 5 24, ages 10–17, 12 weeks
Cohen et
PTSD
Results
Design
Study
TABLE 2. Studies comparing medication and psychotherapy
al.[19]
Follow-up
Review: Advances in Pharmacotherapy for Pediatric Anxiety
79
Medication studies. DeVeaugh-Geiss et al. compared clomipramine (tricyclic antidepressant, TCA) to
placebo.[20] Clomipramine provided greater reduction
in OCD symptoms versus placebo (37 versus 8%) (see
Table 1). During the study, there were four discontinuations of treatment due to anticholinergic effects.
However, many participants remained in treatment with
clomipramine for 1 year and demonstrated improvement. Among the trials that compared the effects of
different SSRIs for treatment of OCD, March et al.
found that sertraline led to a greater number of
responders to treatment than placebo (42 versus 26%)
(see Table 1).[21] Cook et al. conducted a 1-year
extension of sertraline (for participants from either
group, medication versus placebo) and found that 67%
of the sample responded to treatment (see Table 1).[22]
In a study examining the effects of fluoxetine, Geller
et al. found that fluoxetine led to a greater number of
responders to treatment compared to placebo (49 versus
25% placebo) and symptom improvement (see
Table 1).[23] However, Liebowitz et al. found that,
after 8 weeks, there were no significant differences
between the fluoxetine group versus the placebo group
(see Table 1).[24] After another 8 weeks, fluoxetine led
to improvement in OCD symptoms and more treatment responders (57 versus 27% placebo). Riddle et al.
found that fluvoxamine was significantly effective in
reducing OCD symptoms (25 versus14% placebo) (see
Table 1).[25] Adverse events, which were similar across
studies with the SSRIs, included headache, nausea,
weight loss, insomnia, and agitation.
In a 16-week open trial of paroxetine versus placebo
followed by a blinded 16-week randomized discontinuation phase, Geller et al. found that the presence of
additional diagnoses decreases the response rate in the
open-label treatment phase (see Table 1).[26] The
population in this study had the primary diagnosis of
OCD; however, 57.6% of the participants had at least
one additional psychiatric disorder and 30.4% had
multiple other diagnoses. The overall response rate to
the open-label treatment phase was 71%; however, the
response rates in participants with the following
comorbid diagnoses were significantly less than those
with only an OCD diagnosis (Po.05): attention deficit
hyperactivity disorder (56%), tic disorder (53%), and
oppositional defiant disorder (39%). Additional comorbid diagnoses led to greater relapse rates as follows:
46% for one or more comorbid disorders (P 5.04) and
56% for two or more comorbid disorders (Po.05)
compared to 32% without any comorbidity.
In a 10-week study that randomized entrants to
paroxetine or placebo at the beginning of the study,
Geller et al. found that paroxetine led to greater
improvement in OCD symptoms than placebo (and
greater number of treatment responders, 65% with
paroxetine versus 41% with placebo) (see Table 1).[27]
Upon discontinuation of medication, nausea and
vomiting were twice as likely in the paroxetine group
than in the placebo group.
Depression and Anxiety
80
Rynn et al.
Comparative trial. The Pediatric OCD Treatment Study (POTS) compared CBT alone (including
cognitive training and exposure and response prevention), sertraline alone, their combination, and pill
placebo (POTS Team).[28] The combined treatment
was found to be more effective in reducing symptoms
than the other three conditions (P 5.008 CBT
alone, P 5.007 sertraline alone, P 5.001 placebo) (see
Table 2). Both CBT alone and sertraline alone proved
to be more effective than placebo (P 5.003 CBT,
P 5.007 sertraline). In terms of number of participants
demonstrating superior response to treatment, the
combination treatment and CBT did not differ
significantly (54 and 39%, respectively). Furthermore,
medication did not differ from placebo.
SCHOOL REFUSAL
Jessica, age 7, has been complaining of daily stomach
aches in school. She often visits the school nurse and
frequently calls home, asking her parents to pick her up
because her stomach hurts. She also has difficulty getting
ready for school in the morning and lately she has been trying
to convince her mother to let her stay home. Going to school
makes her feel really shaky and she feels like she can’t take a
deep breath when she walks up the front steps of the school
building.
Medication studies. Four medication RCTs have
focused on treating school refusal in children and
adolescents with TCAs and have shown mixed results.[29–32] These inconsistencies are likely caused by
different diagnoses/comorbidities, varying medication
dosages, small sample sizes, and the inclusion of
participants in additional nonstandardized psychotherapies.[33] Gittelman-Klein and Klein found that
medication (imipramine) was significantly better for
treating school refusal in children as compared to
placebo, with 81% in the treatment group returning to
school (as compared to 47% in the control, Po.05) (see
Table 1).[34] However, Klein et al. also compared
imipramine to placebo for children with a primary
diagnosis of separation anxiety disorder (71% with
school refusal) and failed to find differences between
groups (see Table 1).[35]
Finally, Berney et al. tested clomipramine, whereas
Bernstein et al. evaluated alprazolam and imipramine in
comparison to placebo for school refusal.[36,37] Neither
study had positive findings (see Table 1). Both
Bernstein et al. and Gittleman-Klein and Klein
reported dry mouth, drowsiness, dizziness, constipation, and nausea, with most occurring in the Imipramine groups. Klein et al.[35] reported more adverse
effects, including mild-to-moderate dry mouth and
irritability, and outbursts of anger in the moderate-tosevere range.[35] Significantly, more side effects occurred
in the treatment than in the placebo group.
Comparative trial. Bernstein et al. compared
CBT plus imipramine to placebo plus CBT for school
refusal.[38] They focused on adolescents with comorbid
Depression and Anxiety
anxiety and depressive disorders, and found that at
posttreatment, the imipramine plus CBT group’s
weekly attendance was significantly more improved
(70 versus 28% of the time, Po.01) and there were
significantly more participants considered ‘‘remitted’’
(weekly attendance of 75% or more school hours) than
in the CBT plus placebo group (54 versus 17%, Po.01)
(see Table 2). Depressive symptoms were also significantly more reduced in the combination group as
compared to the group with the placebo (Po.05).
Medication seemed to be well tolerated, as only one
child dropped out after having a side effect related to
treatment (i.e. manic symptoms). However, many
children in both groups were still symptomatic at
posttreatment. At the 1-year follow-up, 64% of those
who had participated still met the criteria for an anxiety
disorder, whereas 33% met criteria for a depressive
disorder.[39] In addition, 78% were in outpatient
therapy and 68% had been prescribed psychotropic
medication.
SUMMARY OF RANDOMIZED CONTROL
TRIALS
The data from these studies have shown that there
are efficacious options for the range of pediatric anxiety
disorders: CBT, medication, and their combination.
Based upon present available data, SSRIs are the first
choice of medication if indicated given the side effect
profile for this class of medication. There is preliminary evidence for using venlafaxine ER for pediatric
GAD and SAD. Due to the safety profile of TCAs, they
are not used as first-line and the efficacy evidence does
not support its use. The CAMS (Walkup et al.[40]) and
POTS[28] studies have demonstrated efficacy in combining CBTand SSRIs as well as CBTor an SSRI alone
for treating certain pediatric anxiety disorders.[28,40] In
both studies, the combined approach proved to be
more effective than monotherapy with either CBT
alone or SSRI alone. However, in a study conducted by
Beidel et al.[18] it was found that a group on BT/SET-C
performed better in treating SAD in children than an
SSRI.[18] Recent large-scale trials for social phobia and
OCD did not demonstrate long-term benefit of adding
antidepressant medications to exposure-based therapy;[41,42] similar findings were obtained for studies
that intend to augment exposure-based therapy with
benzodiazepines.[43]
Certainly, there have been major advances in the
available evidence for the use and efficacy of medication treatment for childhood anxiety. However, limitations exist. We need to determine how to enhance
treatments for partial and nonresponders to treatment.
Most studies discussed here did not compare follow-up
samples to controls, in order to assess if findings were a
result of treatment or maturity. We do not know the
long-term impact of chronic medication treatment for
children and adolescents.
Review: Advances in Pharmacotherapy for Pediatric Anxiety
NOVEL
PSYCHOPHARMACOLOGICAL
TREATMENTS
Although SSRI medications and CBT have both
demonstrated efficacy in the treatment of pediatric
anxiety disorders, approximately 20–35% of individuals
receiving these treatments do not benefit.[28,40] Moreover, children and adolescents are frequently averse to
engaging in the anxiety-provoking exposures that
define CBT for anxiety. Consequently, the identification of new treatments that may enhance the treatment
of pediatric anxiety is a much needed area of research.
Over the last decade, a number of novel compounds
have garnered attention as potential pharmacological
treatments for anxiety. Several of these compounds
influence the N-methyl-D-aspartate system (NMDA),
which has recently been associated with emotional
learning and fear extinction.[44] In this section, we
will review six compounds—D-cycloserine (DCS),
N-Acetylcysteine, Memantine, Riluzole, anticonvulsant
medications, and Propanolol—and outline research
indicating their efficacies in treating anxiety disorders
in both adults and children.
D-CYCLOSERINE
Of the glutamatergic compounds being considered in
the treatment of anxiety, DCS has been the most
studied. DCS is a partial receptor agonist of the
N-methyl-D-aspartame system that is believed to
consolidate the learning that occurs during exposure
to anxiety-provoking situations.[45] The ability of DCS
to facilitate ‘‘exposure learning’’ was first supported by
animal research. Walker et al. conditioned rats to fear a
light, by pairing the light with a shock in the rats’
feet.[46] The rats were then administered either DCS
or saline, and half were provided with extinction
training to the light while the others did not. Only
those rats who received both DCS and extinction
training exhibited a reduced fear response to the light.
The fact that rats receiving DCS, but not extinction
training, did not exhibit a reduced fear response
suggested that DCS facilitates the extinction that
occurs during prolonged exposure, but does not itself
cause a reduction in fear. A subsequent animal study by
Ledgerwood et al.[45] found that DCS administration
was associated with a reduced fear response when
administered after extinction training, suggesting that
DCS may influence memory consolidation.
Subsequent research has examined the efficacy of
DCS as an adjunct to exposure treatment in humans.
Double-blinded clinical trials have demonstrated that
exposure therapy augmented by DCS was superior to
exposure therapy augmented by placebo in the treatment of specific phobia of heights,[47] social phobia,[48,49] and panic disorder.[50] Moreover, two studies,
examining the additive effects to exposure and
response prevention for OCD in adults, found that
81
the DCS and placebo groups did not differ in
OCD severity at posttreatment, but the DCS group
exhibited gains more quickly during treatment than
did the placebo group.[51,52] Other studies have found
that the augmentation of CBT did not lead to greater
treatment gains than CBT by itself or augmented
with a placebo in the treatment of OCD[53] or spider
fear.[54]
A recent meta-analysis by Norberg et al.[55] suggested several factors that may impact the efficacy of
DCS as an adjunct to CBT. First, they proposed that a
ceiling effect may exist in which the added benefit of
DCS decreases with milder cases of anxiety. That is,
cases of mild or moderate anxiety may receive such a
large benefit from exposure treatment that there is little
added gain to be made with DCS augmentation. This
argument is supported by the failure of DCS to
improve the efficacy of exposure treatment in subclinical spider-fearing individuals[54] or in individuals
trained to exhibit a fear response.[56] Second, they
argued that DCS is most efficacious when administered
immediately before or after exposure therapy. Finally,
they proposed that DCS’ major contribution may
be to increase the speed or efficiency of exposure
treatment. This is consistent with the findings of
Wilhelm et al.[51] and Kushner et al.[52] that DCS was
associated with quicker gains, but not greater gains at
posttreatment.
In terms of safety, DCS is approved by the US Food
and Drug Administration (FDA) at chronic doses of
1,000–2,000 mg/day for pediatric tuberculosis treatment. At this dosing, there are more serious infrequent
adverse events, such as confusion, tremor, vertigo,
paraesthesias, and seizures.[57] However, dose range for
augmentation treatment for psychiatric disorders
ranges shows mild adverse events of sedation, increased
anxiety, restlessness, and headache.[57]
In the pediatric population, there is one preliminary
study of CBT augmented with DCS for OCD in
children ages 8–17 who were randomized to receive
CBT plus DCS (N 5 15) versus CBT plus placebo
(N 5 15). Study participants received the DCS or pill
placebo 1 hr before the exposure sessions which were
held at least 5 days apart. The two treatment arms were
found not to be statistically different, but the CBT
plus DCS group showed small-to-moderate treatment
effects (d 5 .31–.47) on the primary outcome measures[58] and no reported adverse events. However,
the animal and adult literature provides promise that
DCS may serve as a potentially efficacious adjunct to
CBT for children and adolescents with anxiety
disorders, especially considering the favorable side
effect profile and the benefit of not requiring daily
dosing. Animal studies suggest chronic dosing of
DCS does not provide a significant improvement
for learning or extinction as compared to acute
administration.[59] Based on the studies reviewed
above, DCS may be most beneficial for cases in which
CBT by itself has been unsuccessful or when there is
Depression and Anxiety
82
Rynn et al.
a need for rapid treatment gains (e.g. anxiety leading to
school refusal).
RILUZOLE
Riluzole is a potent antiglutamatergic agent that
reduces glutamatergic neurotransmission in several
ways, including inhibition of glutamate release,
inactivation of voltage-dependent sodium channels in
cortical neurons, and blockade of GABA reuptake.[60,61]
Because of its antiglutamatergic effects, Riluzole has
been targeted as a potential treatment for anxiety
disorders. A number of adult case studies have
demonstrated the efficacy of Riluzole in the treatment
of OCD[62] and trichotillomania,[63] as well as disordered eating and skin-picking behavior.[64] In a series
of case studies, Pittenger et al.[65] administered
Riluzole 50–100 mg BID to 13 adults with treatmentrefractory OCD. Seven of 13 participants exhibited a
greater than 35% reduction in the YBOCS after 12
weeks of treatment augmented by Riluzole, and
Riluzole was well-tolerated by all participants. Similarly, an open-label study by Coric et al.[66] found that
Riluzole augmentation led to a greater than 35%
decrease in the YBOCS for 7 of 13 adults receiving
treatment for treatment-refractory OCD.
Riluzole has also demonstrated some efficacy as an
augmenting agent in the treatment of GAD. In an
open-label trial, Mathew et al.[67] administered Riluzole 100 mg/day to 18 adults with GAD. No other
treatments were administered during the 8-week study
period. At posttreatment, 12 participants exhibited
improved symptoms according to the Hamilton
Anxiety Rating Scale. In parallel to this study, 14
participants and 7 healthy controls for comparison
completed an imaging protocol involving 3 1H MRS
scans at baseline, 24 hr following medication administration, and at the end of treatment. Mathew et al.[68]
demonstrated that improvement in GAD symptoms
while receiving Riluzole treatment was associated with
increases in hippocampal N-acetylaspartate (NAA), a
putative marker for neuroplasticity, whereas hippocampal NAA decreases were observed in Riluzole
nonresponders at the end of treatment. The presence
of increased NAA suggests modulation of the glutamatergic system, which for anxiety disorders may
provide neuroprotection and enhancement of neural
processes.[69] Additionally, Ginsberg[70] completed a
similar open-label study in which 18 adults with GAD
were administered Riluzole 50 mg BID with no other
treatments for 8 weeks. Approximately half the
participants exhibited remission of GAD symptoms at
8 weeks (44% of all participants, 53% of completers),
and a higher percentage demonstrated clinically
significant symptom improvement (67% of all participants, 80% of completers). One study, examining
Riluzole’s efficacy and safety in a pediatric population,
has also yielded preliminary promising results. Six
children meeting criteria for OCD (ages 8–16) were
Depression and Anxiety
administered Riluzole daily (maximum daily dose 5
120 mg) for 12 weeks during an open-label trial by
Grant et al.[71] At posttreatment, four of six participants
exhibited decreased OCD symptoms, according to
the CYBOCS, and improved overall functioning,
according to the CGI. All participants demonstrated
adequate tolerance of Riluzole, with no serious adverse
events reported. Presently, the NIMH Pediatric
Developmental Neuroscience branch is conducting a
double placebo-controlled study comparing Riluzole
versus placebo in pediatric OCD youth, which allows
for comorbid autism spectrum disorders.
In general, Riluzole seems to be well-tolerated by
both adults and children. In one study, common
reported side effects included headache, nausea, and
fatigue.[65] Elevations in transaminases were reported
for some participants in three studies,[65,66,71] but none
of these elevations led to discontinuation of Riluzole.
MEMANTINE
Memantine is an NMDA receptor antagonist that is
believed to provide neuroprotection against glutamatergic neurotoxicity.[72] It received FDA approval for
the treatment of Alzheimer’s disease; but, like other
agents that impact the glutamatergic system, memantine has recently been tested in the treatment of anxiety
disorders, OCD in particular. Memantine, in combination with fluvoxamine, was found to reduce compulsive
scratching in mice more so than fluvoxamine alone.[73]
In humans, Stewart et al.[74] conducted a single-blinded
study, in which memantine (mean final dose 5 18 mg/
day) was added to the treatment regimens of 50% of
participating individuals at an intensive residential
treatment program for OCD. They found that the
memantine group exhibited greater decrease in OCD
symptoms and greater increase in overall functioning
than did the control group. Published case studies in
which memantine was used as an augmenting agent
have yielded mixed results. Pasquini and Biondi[75]
reported a clinically significant decrease in OCD
symptoms for one individual, but not another receiving
memantine augmentation (15 mg/day), and Aboujaoude[76]
found that 6 of 14 individuals receiving memantine
augmentation (20 mg/day) were considered responders
(25% or greater decrease on CYBOCS) after a 12-week
trial. Finally, Poyurovsky found a positive effect of
memantine augmentation (20 mg/day) on an adult
OCD patient after 3 weeks.[77] Memantine has not
yet been formally studied in children or adolescents
with OCD, although Hezel et al.[78] reported considerable improvement when memantine (5 mg/day) was
added to citalopram and CBT for a 15-year-old female
with severe OCD symptoms (CYBOCS 5 36). The
participant exhibited maintained improvement without
any negative side effects, after 9 months of continuous
memantine augmentation. All the above studies reported good tolerance of memantine, and a study of
memantine in the treatment of mania[79] also reported
Review: Advances in Pharmacotherapy for Pediatric Anxiety
tolerance, with the most common side effects being
relatively minor (e.g. nausea, constipation, headache).
ANTICONVULSANT MEDICATIONS
Because of their purported effects on the glutamate
and GABA systems, anticonvulsant medications, including topiramate, gabapentin, and pregabalin, have
been the focus of some study in the treatment of
anxiety disorders. Whereas these medications seem to
have several mechanisms of action, it is believed that
the blockade of L-type calcium channels and inhibitory
effects on GABA-ergic receptors may be related to the
reduction of anxiety.[80] In adults, open-trial and case
studies have demonstrated some support for anticonvulsant medications in the treatment of anxiety
disorders.[80] The strongest study of anticonvulsant
medications was a double-blind fixed-dose study of
pregabalin (150 or 600 mg daily) in the treatment of
adults with GAD.[81] Individuals receiving pregabalin
at either dose exhibited greater improvement in anxiety
symptoms, as measured by the Hamilton Anxiety
Rating Scale, than individuals receiving placebo, and
pregabalin was well-tolerated. These findings were
replicated by another double-blind trial of pregabalin
in the treatment of GAD.[82] However, anticonvulsants
have been associated with a number of negative
psychiatric side effects, including depression, aggressive behavior, and psychosis.[83,84] Because of this side
effect profile, as well as the lack of research demonstrating the efficacy of anticonvulsants in pediatric
populations, the use of anticonvulsants for pediatric
anxiety is currently not a feasible treatment option.
PROPANOLOL
Propanolol is a -adrenergic blocker that inhibits
memory consolidation caused by the -adrenergic
system.[85] Based on this discovery, propanolol has
been studied as a potential method to prevent and treat
PTSD. Pitman and Sanders conducted a double-blind
trial comparing propanolol (40 mg) four times daily to
placebo in the treatment of PTSD.[86] PTSD severity,
as measured by the Clinician Administered PTSD scale
(CAPS), did not differ between the two groups 1 month
after treatment, which may be attributed to an outlier
with an extremely high CAPS score in the propanolol
group. However, the percentage of individuals continuing to meet criteria for PTSD was lower in the
propanolol group (18%) than the placebo (30%) 1
month after treatment, and the propanolol group
demonstrated reduced physiologic response compared
to the placebo group when exposed to traumatic
imagery. There was no difference reported between
the groups at the 3-month follow-up, although the
propanolol group, compared to the placebo group,
continued to display reduced physiologic response to
traumatic imagery. Case studies,[87,88] analog studies,[89] and open trials[90] have also suggested that
propanolol may treat PTSD and possibly prevent its
83
onset. Of note, propanolol has not been studied in
children who have experienced trauma or who meet
criteria for PTSD. Whereas propanolol may be a
promising treatment for PTSD in both adults and
children, its use in modifying an individual’s memories
has raised some ethical concerns (see Bell[91]).
SUMMARY
Medications influencing the glutamatergic, GABAergic, and -adrenergic systems hold promise as
potential treatments for anxiety disorders. Most of
the compounds mentioned above were well-tolerated
in clinical trials and provide potential additional
treatment options to consider. To this point, however,
most research on the compounds listed above has been
case studies or open trials, with the exception of several
double-blind studies examining DCS. Furthermore,
none of these compounds have been studied sufficiently
in pediatric populations. Additional research is needed
to determine the efficacy and safety of these medications in the treatment of pediatric anxiety disorders.
PRESENT PRACTICE FOR
PEDIATRIC MEDICATION
TREATMENT AND MONITORING
Although there is evidence supporting a combination
of CBT and medication for treating child and
adolescent anxiety, both treatments alone are also
empirically supported options. This is useful, as
combined treatment may not be feasible or accepted
by a child and family. Potential benefits and risks of
each treatment should be discussed to help families
make an educated decision. Medication treatment is
recommended when a child’s symptoms are in the
moderate-to-severe range where the child cannot
function (e.g. cannot eat or sleep, cannot start CBT)
or when the child has been in CBT for 8–12 weeks, but
is not improving.)
Currently, SSRIs are considered first-line treatment,
as these medications have few side effects and
laboratory testing is not indicated. Children or
adolescents who do not respond to an SSRI may
benefit from venlafaxine ER, which is considered a
second- to third-line medication that should involve
monitoring of a child’s weight, vital signs, and
cholesterol based upon the available data that suggests
some children may experience weight loss, increases in
cholesterol, and vital sign changes.[15] It has been
suggested that medication treatment may also be
augmented for complicated and treatment-resistant
cases with buspirone, benzodiazepines, stimulants, a
second SSRI, atypical antipsychotics, and TCAs;
however, there is little to no empirical evidence to
support these options.[7,92,93] Beginning with the lowest
dosage of medication for the first 7 days is recommended. However, children tend to metabolize
Depression and Anxiety
84
Rynn et al.
medications quickly and often require the same dosages
as adults. Children and families should be told what to
expect in terms of side effects, what to do when they
occur, and how the clinician will manage potential
adversities. Addressing the child directly is also
essential, as parents are not always aware of side effects
(i.e. an adolescent may not reveal that medication has
reduced their sex drive). If after 1 week the child is
tolerating the medication with minimal side effects, the
dose can slowly be titrated upwards over several weeks
until a treatment response occurs and the child is
taking a dose known to be clinically efficacious. After
8–12 weeks, the medication treatment should be
reevaluated to determine if it is being tolerated,
reducing the target anxiety symptoms, and improving
functioning. Systematic evaluation of a child’s progress
over time helps to create an evidence-based treatment
plan, to review the child’s progress over time, and to
make treatment modifications as needed.
The FDA recommends making weekly appointments
with the child for 4 weeks before switching to every
2 weeks for 4 weeks.[94] Medication management
appointments should then occur at 12 weeks and then
every month. This guideline may be difficult to
implement due to lack of physician availability,
insurance coverage, and families’ schedules. A clinician
could use a phone session to monitor clinical
progress and the development of adverse events. When
a child or adolescent on an SSRI has a significant
reduction in anxiety or depressive symptoms that has
been maintained for more than 1 year, a medicationfree trial during a low-stress time period (e.g. vacation)
should occur. However, if the child begins to
relapse, the clinician should immediately reinstate the
medication.[95]
Unfortunately, we do not yet know moderators or
predictors of treatment response, and so we must often
rely on educated trial and error. First, it is important to
make sure that the child has been on adequate dose of
the medication for a sufficient amount of time. If
before 12 weeks, results should be reassessed at the end
of this time period. Second, dosage should also be
assessed. If a child has no benefit or adverse side effects,
increasing the dose slowly over time is appropriate.
Third, it is important to determine if the child is
actually taking the medication. In cases of medication
non-compliance, it is important to discuss this
issue with the child and family to determine the root
of the problem and evaluate potential solutions
(e.g. alarm reminder, more psychoeducation, and
alternative treatment options). If medication is still
not effective, another trial of a different medication can
be attempted.
As discussed, a combination of CBT and medication
treatment can help significantly more children and
adolescents suffering from an anxiety disorder. Even
before large multisite RCTs, researchers and clinicians
have advocated for the combination of psychosocial
and pharmacological treatments. Arguments have been
Depression and Anxiety
put forth to support the use of combination treatments
as follows[96]: (1) for children with severe anxiety, two
treatments provide greater dosage, which may result in
a quicker positive outcome; (2) comorbid diagnoses or
various outcomes may respond to different treatments.
For example, a child with separation anxiety disorder
may show great symptom reduction from medication,
but needs to participate in exposure therapy to return
to school, whereas a child with comorbid ADHD and
anxiety may also benefit from a combination of
psychostimulant medication and CBT, such as classroom behavior management and parent training; and
(3) when children partially respond, augmenting the
first treatment with another intervention can increase
the effect in one or more symptom areas, such as when
a child already in CBT for OCD is prescribed an SSRI
for comorbid depression. Combining psychosocial and
psychopharmacological approaches to treatment also
engenders a multidisciplinary team effort that provides
mental health professionals with a variety of opportunities to learn from those with different backgrounds,
fostering innovative ideas and improved clinical care.
CONCLUSION
The field of pediatric psychopharmacology for
anxiety disorders has made great strides in examining
medication treatment in terms of efficacy, safety, and its
use in combination with psychotherapy. The evidence
supports the use of medication monotherapy for
anxiety disorders with SSRIs being first-line choice.
However, cognitive behavioral therapy is an efficacious
treatment for all anxiety disorders. In the case of
pediatric OCD, excellent responder status was achieved
by CBT monotherapy and combination treatment,
whereas the medication arm did not differ from
placebo. There are children who will benefit from
starting with combination treatment from depending
on illness severity, presence of comorbid diagnoses, and
the child’s ability to participate in treatment.
The field continues to be informed by the development and use of new compounds in adult populations
suffering from the same disorders. However, safety
concerns and the limited knowledge about the impact
of mediation exposure on brain development, especially
for long-term exposure, necessitate continued research
of potential effects from presently used medications
and cautious exploration with new compounds. In
reviewing animal studies and the development of
anxiety disorders in humans, Leonardo and Hen[91]
discuss the importance of studying critical brain
developmental windows where the interaction between
environmental stressors and genetic makeup shape the
formation of the anxiety neural circuitry.[97] The
manipulation of the serotonergic system in animal
models during these periods seem to impact the
baseline anxiety levels seen in the mature animal. As
these processes are better understood in animal models,
this will lead to a better understanding of the potential
Review: Advances in Pharmacotherapy for Pediatric Anxiety
impact of various classes of medication on the
developing brain.[98]
At this time, there is limited information on the
treatment approach for partial and nonresponders to
first-line treatments. Research is needed to evaluate the
use of second- and third-line treatments in order to
determine the best augmentation and sequence strategies. Treatment strategies may be informed by the
identification of clinical or biological traits that may
help predict the best treatment selection for a specific
child. An example of this is the finding that greater
activity in the left amygdala predicts medication
response.[99] As the fields of clinical therapeutics and
biological research continue to integrate to pursue
these lines of inquiry, there is hope for continued
advancement for the development of targeted treatments for those children who do not respond to the
present available treatments.
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