Psychopharmacologic Treatment of Children and Adolescents with Anxiety Disorders Jeffrey R. Strawn, MDa,b,*, Dara J. Sakolsky, MD, PhDc, Moira A. Rynn, MDd

KEYWORDS • Benzodiazepine • Generalized anxiety disorder • Selective serotonin norepinephrine reuptake inhibitor • Selective serotonin reuptake inhibitor • Separation anxiety disorder • Social phobia KEY POINTS • Anxiety disorders often first emerge during childhood and adolescence and adversely affect social and family relationships and school performance. • Children and adolescents with anxiety disorders are also more likely to report suicidal ideation or to attempt suicide than healthy subjects. • Advances in pediatric psychopharmacology raise a number of opportunities to potentially decrease morbidity in youth with anxiety; emerging literature suggests that selective serotonin reuptake inhibitors and cognitive– behavioral therapy may modulate the activity of specific structures within central brain fear circuits. • Neuroimaging markers of treatment response in pediatric anxiety will help to identify the specific neural circuits involved in successful treatment. • Genetic markers of may enhance understanding of the molecular pathophysiology of treatment response in pediatric anxiety disorders. • Biosignatures (eg, panel of genetic, neuroimaging, and/or physiologic biomarkers) in the future may be used to guide individualized treatment recommendations.

INTRODUCTION

Anxiety disorders often first emerge during childhood and adolescence,1,2 and adversely affect social and family relationships as well as school performance.3 DISCLOSURES: Dr Strawn has received research support from Eli Lilly, Shire and from the American Academy of Child and Adolescent Psychiatry. Dr Sakolsky has received research support from NARSAD and NIMH. Dr Rynn has received research support from Eli Lilly, Shire, and Pfizer, and from the NIH and NICHD. a Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, College of Medicine, Cincinnati, OH 45219, USA; b Department of Psychiatry, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45267, USA; c Department of Psychiatry, University of Pittsburgh, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Bellefield Towers, Room 515, 100 North Bellefield Avenue, Pittsburgh, PA 15213, USA; d Department of Psychiatry and New York State Psychiatric Institute (NYSPI), Columbia University, New York, NY, USA * Corresponding author. Department of Psychiatry, University of Cincinnati, Box 670559, Cincinnati, OH 45267-0559. E-mail address: [email protected] Child Adolesc Psychiatric Clin N Am 21 (2012) 527–539 http://dx.doi.org/10.1016/j.chc.2012.05.003 childpsych.theclinics.com 1056-4993/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved.

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Children and adolescents with anxiety disorders are also more likely to report suicidal ideation or to attempt suicide than healthy subjects, and are more likely to report or attempt suicide than those with depression alone. These findings suggest that anxiety disorders heighten the risk of suicidal ideation or suicide attempts in children and adolescents.4,5 However, despite the prevalence of these conditions and their associated morbidity, children and adolescents suffering from anxiety disorders are often not identified and frequently do not receive treatment with psychotherapy or psychopharmacologic interventions.6,7 Psychopharmacologic trials in youth with anxiety disorders (other than obsessive– compulsive disorder [OCD] and posttraumatic stress disorder) have largely focused on studying the “anxiety triad” of symptoms and disorders (eg, the combination of separation anxiety disorder [SAD], generalized anxiety disorder [GAD], and social phobia [SoP]).8 The tendency to evaluate the treatment of these three anxiety disorders (specifically GAD, SAD, and SoP) together has generally been the result of several clinical and theoretical issues. For example, these anxiety disorders are (1) highly comorbid, (2) are considered physiologically distinct from other child onset anxiety disorders (eg, OCD or posttraumatic stress disorder), and (3) they have shown similar responses to treatment with pharmacotherapy (eg, selective serotonin reuptake inhibitors [SSRIs] and cognitive behavioral therapy [CBT]).9 –11 However, several studies have recently focused on specific anxiety disorders (eg, GAD or SoP) in these populations. In this review, we have summarized all randomized, controlled trials of SSRIs, serotonin norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, and other agents (eg, buspirone and tricyclic antidepressants) that have included pediatric patients with non-OCD, non-posttraumatic stress disorder anxiety disorders. GENERALIZED ANXIETY DISORDER Sertraline

In the first placebo-controlled trial of the SSRI sertraline to be conducted in youth with GAD, children and adolescents, aged 5–17 years (n ⫽ 22), were treated with fixed-dose sertraline (50 mg/d) for 9 weeks. Compared with placebo-treated youth, significant improvement was noted in the sertraline-treated patients on the Hamilton Anxiety Rating Scale,12 Clinical Global Impression—Severity (CGI-S; from 1 [not mentally ill] to 7 [severely ill]) and CGI—Improvement (CGI-I; from 1 [very much improved] to 7 [very much worse]) scores. Additionally, the authors of this study controlled for the severity of co-occurring depressive symptoms and observed a highly significant “main treatment effect for anxiety,” but not for depression.13 No differences in side effects were observed between the sertraline-treated patients and those who received placebo. In addition, sertraline was recently compared with placebo, CBT, and their combination (sertraline plus CBT) in the Child/Adolescent Anxiety Multimodal Study (CAMS) in which GAD was present in 78% of the 488 patients.8 In CAMS, sertraline was found to be superior to placebo and equally as effective as CBT. Fluoxetine

A small study of 14 youth with GAD revealed that treatment with flexibly dosed fluoxetine (5– 40 mg/d) or CBT was associated symptomatic improvement in youth with GAD14 and revealed increased activation of the right ventrolateral prefrontal cortex in response to pictures of angry faces after treatment with both fluoxetine and CBT, suggesting that increased activity within the ventrolateral prefrontal cortex may have compensatory function in youth with GAD.14 In addition, several studies have

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evaluated the efficacy of fluoxetine in patients with GAD or overanxious disorder (DSM-III-R forerunner for GAD) in studies of mixed anxiety disorders in youth,15–17 and these are discussed later in the section on mixed anxiety disorders. Venlafaxine

The SNRI venlafaxine has been evaluated in 2 randomized, 8-week, placebocontrolled trials in youth diagnosed with GAD, aged 6 –17 years (n ⫽ 323).18 Extended-release (ER) venlafaxine was initiated at 37.5 mg/d in all participants. For youth weighing between 25 and 39 kg, the highest dose allowed was 112.5 mg/d; for patients weighing 40 kg and greater it was 225 mg/d. In this report, which includes data from 2 identically designed studies (Study 1 and Study 2), venlafaxine ER was superior to placebo in producing improvements in scores on the GAD section of the Columbia K-SADS as well as the Pediatric Anxiety Rating Scale (PARS),19 Hamilton Anxiety Rating Scale,12 and Screen for Anxiety Related Emotional Disorders (parent and child)20 scores only in Study 1 (P⬍.001), but failed to reach significance in Study 2 (P⬍.06). In the pooled analysis of Study 1 and Study 2, venlafaxine ER, compared with placebo, demonstrated significant differences for improving anxiety symptoms (P⬍.001) and had a higher response rate (69% vs 48%; P⬍.04).18 Children and adolescents who received venlafaxine were more likely to experience asthenia, pain, anorexia, and somnolence as well as weight loss compared with those receiving placebo.18 Buspirone

To date, 2 open-label studies have evaluated the efficacy and tolerability of the 5-HT1A agonist buspirone in pediatric patients with overanxious disorder (now defined as DSM-IV-TR GAD). Kutcher and colleagues21 reported that over 6 weeks of treatment with flexibly-dosed buspirone (15–30 mg/d), anxiety significantly improved in youth with overanxious disorder. Subsequently, Simeon22 reported that in a sample of 13 children and adolescents (9 of whom had primary or secondary diagnoses of overanxious disorder), anxiety symptoms significantly improved over 4 weeks of treatment. In addition, buspirone was generally noted to be well tolerated, although some patients experienced sedation, nausea, stomach aches, and headaches.22 Two randomized, placebo-controlled trials of buspirone have examined the efficacy and tolerability of this agent in pediatric patients (age range, 6 –17 years; n ⫽ 559). In these studies, which utilized 15– 60 mg of buspirone per day, no significant differences between buspirone and placebo were noted for GAD symptoms,23 despite pharmacokinetic studies of this agent which have revealed plasma exposure to buspirone [and its active metabolite, 1-(2-pyrimidinyl)-piperazine] are equivalent or greater in pediatric patients compared with adults.24 Benzodiazepines

Despite the common use of benzodiazepines for the treatment of anxiety disorders in adults,25–27 there are few studies completed with anxious youth and the results have been mixed. In 1 open-label trial, 12 adolescents with overanxious disorder (DSMIII-R criteria) were treated with open-label alprazolam (0.5–1.5 mg/d) for 4 weeks and significant improvements were noted in terms of anxiety and insomnia.22 Of note, alprazolam was generally well tolerated, despite some sedation, agitation, headaches, and nausea.28 A double-blind, placebo-controlled trial of alprazolam in youth aged 8 to 16 years (n ⫽ 30) with overanxious disorder (DSM-III-R criteria) found no difference between alprazolam and placebo on a clinical global rating of improvement. However, this study may have failed to find a difference between groups

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because it was underpowered. Alprazolam was well-tolerated, with some reports of fatigue and dry mouth; there were no reports of withdrawal symptoms.28 SOCIAL PHOBIA Paroxetine

In a multicenter, double-blind, placebo-controlled trial of paroxetine, Wagner and colleagues29 randomized 322 youth with SoP to paroxetine or placebo. In this 16-week study, the last-observation carried forward analyses revealed a greater response (by CGI-I score) for paroxetine (78% response) as compared with placebo (38.3% response). Insomnia, decreased appetite, and vomiting were among the most common side effects (experienced at least twice as often in the medication group than the placebo group), although the medication was generally well tolerated. In addition, 4 paroxetine-treated patients expressed suicidal ideation or had threatened suicide (versus none in the placebo group). Finally, and of clinical importance, upon discontinuation, SSRI withdrawal symptoms including nausea, dizziness, and vomiting were experienced twice as frequently by the paroxetine-treated patients than those who received placebo.29 Venlafaxine ER

The efficacy of venlafaxine ER has been evaluated in a randomized, double-blind, placebo controlled trial of 293 outpatient children and adolescents (age 8 –17 years; mean, 13.6) with SoP.30 Venlafaxine ER was initiated at 37.5 mg/d and titrated to a maximum dose over 16 weeks. Specifically, in youth weighing between 25 and 33 kg, the maximum dose was 112.5 mg/d, whereas in patients weighing between 34 and 49 kg, venlafaxine ER was titrated to a maximum dose of 150 mg/d and in youth weighing more than 50 kg, venlafaxine ER could be increased to 225 mg/d. March and colleagues30 noted that youth receiving venlafaxine ER had a greater reduction in their social anxiety symptoms compared with placebo (response rates in the 2 groups were 56 vs 37%, respectively; Table 1). Although both groups reported mild-tomoderate adverse events, events that occurred at least twice as often as in placebo included asthenia, pain, anorexia, and somnolence. Significant weight loss was noted in patients treated with venlafaxine ER. Also, 3 patients treated with venlafaxine ER developed suicidal ideation, whereas no patients in the placebo group reported suicidal ideation.30 Fluoxetine

In a double-blind, randomized trial, Beidel and colleagues31 compared Social Effectiveness Therapy for Children (SET-C), fluoxetine (forced titration 10 – 40 mg/d), and a pill placebo in children and adolescents (aged 7–17 years) with SoP.31 Patients were randomized to 1 of 3 treatment groups: SET-C, fluoxetine, or pill placebo. Of the SET-C group, 53% no longer met diagnostic criteria (compared with 21.2% of patients treated with fluoxetine and 3.1% of those treated with placebo). There were no severe adverse events reported, although some fluoxetine-treated participants experienced side effects (eg, diarrhea).31 Sertraline

An open-label study of sertraline (mean dose 123 ⫾ 37 mg/d) in children and adolescents (age 10 –17 years; 8 boys and 6 girls) with SoP, evaluated 14 youth during 8 weeks of treatment with sertraline.32 Analysis of CGI-I scores revealed that 36% (5/14) of subjects were responders and 29% (4/14) as partial responders by the end

Table 1 Randomized, controlled trials of SSRIs and SNRIs and atypical anxiolytics in pediatric anxiety disorders Reference Diagnosis

Duration (wks)

Treatment

n

Dose Range (mg/d)

Average Dose

NNT*

Outcome

Walkup et al8

GAD SoP SAD

12

Sertraline CBT Combination Placebo

133 139 140 76

25–200 25–200

146.0 ⫾ 60.8 to 133.7 ⫾ 59.8 mg

3 (3.2–3.5)

CBT, SSRIs, or CBT ⫹ SSRIs ⬎ placebo

Rynn et al13

GAD

9

Sertraline Placebo

11 11

50

Fixed dose

2 (1–2)

Sertraline ⬎placebo

Beidel et al31

SoP

12

Fluoxetine SET Placebo

33 57 32

10–40

Not specified

Wagner et al29

SoP

16

Paroxetine Placebo

163 156

10–50

24.8 mg for all patients, 21.7 mg for children, and 26.1 mg for adolescents

3 (3–4)

Paroxetine ⬎placebo

March et al30

SoP

16

Venlafaxine ER Placebo

137 148

37.5–225

2.6–3.0 mg/kg

6 (4–14)

Venlafaxine ER ⬎placebo

Rynn et al18

GAD

8

Study 1: Venlafaxine ER Placebo Study 2: Venlafaxine ER Placebo

76 77 78 82

37.5–225 37.5–225

5 (4–11)

Study 1: Venlafaxine ER Placebo Study 2: Venlafaxine ER ⫽ Placebo

Birmaher et al17

GAD SoP SAD

12

Fluoxetine Placebo

37 37

20

Fixed dose

4 (3–27)

Fluoxetine ⬎placebo

RUPP40

GAD SoP SAD

8

Fluvoxamine Placebo

61 63

2.9 ⫾ 1.3 mg/kg

3 (2–4)

Fluvoxamine ⬎placebo

BMS, 2010

GAD

8

Buspirone Placebo

Not specified

N/A

Buspirone ⫽ placebo

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Abbreviation: SET, Social Effectiveness Therapy for Children. * Number needed to treat (NNT) for medication versus placebo.

15–60 mg

SET ⫽ fluoxetine ⬎placebo

531

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of the 8-week trial. Response occurred by week 6 and sertraline was generally well tolerated with no subject developing significant behavioral disinhibition, mania, or suicidal ideation. Nausea, diarrhea, and headaches were the most frequently reported adverse events and were generally mild.32 In addition, patients with SoP (82% of sample) were included CAMS, which compared placebo, sertraline, CBT, their combination (sertraline plus CBT) in youth with multiple anxiety disorders8 and is discussed in the mixed anxiety disorders section. Citalopram

No randomized, controlled trials have evaluated the efficacy of citalopram in the treatment of pediatric SoP. One open-label study of citalopram evaluated the efficacy of flexibly dosed citalopram (10 – 40 mg/d, mean dose 35 ⫾ 7 mg/d) in 12 children and adolescents (aged 8 –17 years; mean, 13.4 ⫾ 3) with social anxiety disorder over 12 weeks.33 In this study, 83% of youth reported improvement (as measured by CGI-I); significant improvement was also observed on self-report and parental reports of social anxiety symptoms.33 In general, citalopram was well-tolerated. SEPARATION ANXIETY DISORDER Tricyclic Antidepressants

Several studies have evaluated youth with school refusal in whom SAD and or SoP are often present. In the first, 35 children (aged 6 –14 years) were treated with flexibly dosed imipramine (100 –200 mg/d) and imipramine-treated patients treated with imipramine improved more so than those who received placebo. However, subsequent trials of tricyclic antidepressants in youth with school refusal, overanxious disorder, and SAD have failed to find differences between imipramine34,35 or clomipramine36 and placebo. Finally, Bernstein and colleagues37 compared CBT plus imipramine with CBT plus placebo in 63 adolescents with major depressive disorder and an anxiety disorder, and found clinician and self-report measures of anxiety showed no significant difference between groups. Benzodiazepines

One study has evaluated the efficacy of clonazepam (up to 2 mg/d) in 15 children (aged 7–13 years; 8 males and 7 females) with SAD (SAD, n ⫽ 14; GAD, n ⫽ 5; total, n ⫽ 15). This study was unique in that it utilized a crossover design, which should have been powered to detect a “clearly beneficial effect.”38 No difference in the clinical global improvement scale was observed between the clonazepam-treated and placebo groups. In general, patients experienced frequent side effects (83% clonazepam vs 58% placebo). Drowsiness, irritability, and “oppositional behavior” were the most frequent side effects seen the clonazepam group.38 Of note, most psychopharmacologic trials of youth with “mixed anxiety disorders” have included children and adolescents with SAD in addition to GAD and SoP because of their high comorbidity. For example, in CAMS, more than half of patients met DSM-IV-TR criteria for SAD, thus the results of this placebo-controlled trial of sertraline and CBT,8 which are described in the mixed anxiety disorders would likely be applicable to youth with SAD. PANIC DISORDER

Studies of pharmacologic interventions in youth with panic disorder are rare and many recent studies of pediatric anxiety disorders have excluded patients with panic disorder. In fact, we are only able identify 2 open-label studies of SSRIs in pediatric

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patients with panic disorder. In the first study, several SSRIs (fluoxetine, sertraline, and paroxetine) were evaluated in 12 children and adolescents with panic disorder (mean age, 14.5 ⫾ 3.4 years; 7 girls) over the course of 6 months, and the authors observed that 75% of patients were “much” to “very much improved,” and that SSRIs were generally well-tolerated in this population. Importantly, at the conclusion of the trial, 67% of patients no longer fulfilled criteria for panic disorder, although 4 youth continued to experience “significant residual symptoms.” In this study, a benzodiazepine adjunct (clonazepam and lorazepam) was used in 67% of patients and the authors suggest that “treatment [with a benzodiazepine] might be helpful for patients with severe panic disorder” while awaiting the clinical response to the SSRI.39 Additionally, in a study which is described in greater detail in the mixed anxiety disorders section, Fairbanks and colleagues15 treated 16 children and adolescents with flexibly dosed fluoxetine and noted that only 3 of 5 patients with panic disorder exhibited clinical response.15 To date, we are unable to locate any placebo-controlled trials of any psychopharmacologic treatment in youth with panic disorder. MIXED ANXIETY DISORDERS Fluvoxamine

Fluvoxamine has been evaluated in a double-blind, placebo-controlled trial in youth with anxiety disorders including SAD, SoP, and GAD.40 In this study, 128 children with anxiety disorders were treated with fluvoxamine titrated to 300 mg/d (mean dose, 2.9 ⫹ 1.3 mg/kg) and significant differences were found in CGI-I and endpoint PARS scores (P⬍.001). In addition, fluvoxamine was well tolerated with only abdominal discomfort and increased motor activity occurring more frequently in the fluvoxaminetreated youth than in those who received placebo.40 In addition, a 6-month, open-label extension of this study revealed that 94% of fluovoxamine responders maintained response and 71% (10/14) of the fluvoxamine-treated patients who had not responded to fluvoxamine responded to fluoxetine.41 Fluoxetine

Two open-label studies have evaluated the SSRI fluoxetine in youth with mixed anxiety disorders.15,16 In the first study, youth with mixed anxiety disorders (overanxious disorders, SoP, or SAD) who were not depressed and whom had failed to respond to psychotherapy were treated for 6 months with flexibly dosed fluoxetine for up to 10 months. Birmaher and colleagues17 observed moderate to marked improvement in 81% of patients and noted fluoxetine to be very well tolerated. Later, Fairbanks and colleagues15 evaluated 16 outpatients (aged 9 –18) who had failed psychotherapy and treated them with flexibly dosed fluoxetine (5 mg/d, flexibly titrated to a maximum of 40 mg in children and 80 mg/d in adolescents [mean dose, 0.7 mg/kg] in both groups). Clinical improvement occurred in all patients with current SAD (n ⫽ 10), whereas clinical improvement occurred in 8 of 10 with SoP, 4 of 6 with specific phobia, 3 of 5 with panic disorder, and 1 of 7 with GAD. Fluoxetine was well tolerated and the most frequently reported side effects included drowsiness, sleep problems, decreased appetite, nausea, and abdominal pain. No treatment-emergent suicidality was noted in this trial and the authors concluded that fluoxetine may be effective in “SAD and SoP.” Also of interest, the authors observed that patients with only 1 anxiety disorder tended to respond to lower doses of fluoxetine than patients with multiple anxiety disorders (0.49 ⫾ 0.14 vs 0.80 ⫾ 0.28 mg/kg).15 Birmaher and colleagues17 evaluated the efficacy and tolerability of fluoxetine in a randomized, placebo-controlled trial of youth with GAD, SAD, and SoP (mean age, 11.6 ⫾ 3 years; range, 7–17). In this 12-week trial, fluoxetine was initiated at 10 mg/d

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and was titrated to 20 mg/d at the end of the first week and was generally well tolerated; 76% of the fluoxetine-treated patients completing the trial (versus 84% placebo completion; P ⫽ .39). Compared with placebo, significant improvements were noted in the fluoxetine-treated patients on the Screen for Anxiety Related Emotional Disorders (both child and parent versions) scores, PARS score, CGI-I, CGI-S, and CGAS. Rates of CGI-I scale response were significantly higher in the fluoxetine group than in the placebo group and treatment effects. In addition, a follow-up study suggested that fluoxetine may be effective as a maintenance treatment in children and adolescents with anxiety disorders.42 Sertraline Plus Cognitive Behavioral Therapy

Recently, CAMS evaluated the comparative efficacy of sertraline, CBT, or the combination of sertraline plus CBT (COMB) in patients aged 7 to 17 years (mean, 11.8) with SoP, SAD, GAD, or any combination of these anxiety disorders.8 Sertraline was initiated at 25 mg/d and was titrated to 200 mg/d (mean, 146 ⫾ 61; 25–200). Improvement (CGI-I) scores for the children treated with COMB were greater (80.7%) than for those youth who received CBT (59.7%) or sertraline alone (54.9%). All treatments were superior to placebo in this 12-week study.8 With regard to remission rates after 12 weeks of treatment were 46% to 68% for COMB, 34% to 46% for sertraline, 20% to 46% for CBT, and 15% to 27% for placebo.43 Sertraline was well tolerated and rates of adverse events were similar to placebo. However, those children who received CBT were less likely to report insomnia, fatigue, sedation, restlessness, or fidgeting than those who received sertraline.8 Finally, a recent analysis of remission in this study revealed that predictors of posttreatment remission included younger age, nonminority status, lower baseline anxiety severity, absence of other internalizing disorders (eg, depression), and absence of SoP.43 Atomoxetine

The SNRI atomoxetine has been evaluated in a placebo-controlled trial of children and adolescents (age 8 –17 years) with ADHD and comorbid anxiety (defined as SAD, GAD, SoP, or a combination of these conditions). Atomoxetine was initiated at 0.8 mg/kg per day for 3 days and increased to the target dose of 1.2 mg/kg per day with a maximum dose of 1.8 mg/kg per day; treatment was continued for 12 weeks. Last observation carried forward analysis of PARS scores revealed improvement with atomoxetine versus placebo (effect size ⫽ 0.5) and significant improvements were also noted for ADHD symptoms. In general, atomoxetine was well tolerated.44 TREATMENT GUIDELINES

Over the last 2 decades, substantial advances have been made in both psychotherapeutic and psychopharmacologic treatment of youth with anxiety disorders. Of the available studies of psychotherapy, most have evaluated the efficacy of CBT,45– 47 although several alternate forms of psychotherapy that are efficacious in other types of psychopathology in youth remain understudied in youth with anxiety disorders (eg, interpersonal psychotherapy for adolescents and mentalization-based therapy). As these studies suggest, the SSRIs are considered to be first-line medication treatments for childhood anxiety disorders. Additionally, there are some preliminary data for the use of SNRIs (eg, venlafaxine ER) for GAD and SoP. Because of the lack of positive results and their side effect profile, TCAs are generally not recommended for the treatment of the triad anxiety disorders. The research data are limited in terms of the use of benzodiazepine; however, with careful dosing and monitoring, this class

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of medication may be helpful as adjunctive treatment to the SSRI during the acute phase of treatment. Unfortunately, there are very few medication trials that provide information on the efficacy, tolerability, and safety for long-term medication treatment. Of those that are available, they seem to suggest with continued treatment response is maintained and adverse events are tolerable. However, when considering prescribing medication for a pediatric patient, the clinician needs to consider the risks versus the benefits for this treatment and to convey this information to the parent and child. As reviewed herein, antidepressants can lead to adverse events in 2 main categories: Physical (eg, headaches, gastric distress, and sleep difficulties) and psychiatric (eg, disinhibition, agitation, increased anxiety symptoms, and suicidal ideation and behaviors). Of particular concern is the “black-box” warning placed by the US Food and Drug Administration in 2004 on antidepressant medications, including SSRIs and SNRIs, publicizing a 2-fold increased risk for suicidal thinking or behavior in children and adolescents taking these medications. Bridge and colleagues48 conducted a meta-analysis based on pediatric medication trials including all indications (n ⫽ 39, of which 6 were OCD trials).48 The results showed a small, increased risk of suicidal ideation and attempts for youth treated with antidepressant medications as compared with placebo (0.7%; 95% confidence interval, 0.1%–1.3%) in all studies for both anxiety and depression trials. It was found the number needed to harm was 143 (95% confidence interval, 77–1000) and there were no completed suicides. Table 1 shows the NNT for each of the studies discussed herein. Finally, the field has shown significant, positive, synergistic effects of the combination of psychotherapy and psychopharmacologic interventions,8,43 and current practice guidelines from the American Academy of Child and Adolescent Psychiatry recommend a multimodal treatment approach.49 IMPLICATIONS FOR RESEARCH AND CLINICAL PRACTICE

The exciting advances in pediatric psychopharmacology described herein raise a number of opportunities to potentially decrease morbidity in youth with anxiety. First, distinct lines of research have begun to converge as studies have integrated the clinical effects of successful treatment with SSRIs and psychotherapy with the accompanying changes in the underlying neurophysiology of pediatric anxiety disorders.14,50 In short, this emerging literature suggests that SSRIs and CBT may modulate the activity of specific structures within these central brain fear circuits (those involving the anterior limbic network; see Strawn and colleagues50 for a recent review) and lays the groundwork for studies which may predict treatment outcome based on neural responses obtained in specific functional magnetic resonance imaging tasks.51 Although neuroimaging markers of treatment response in pediatric anxiety will help to identify the specific neural circuits involved in successful treatment, genetic markers may enhance our understanding of the molecular pathophysiology of treatment response in pediatric anxiety disorders. Preliminary data analyses from the CAMS study suggest that genetic variation in GRIK4, the gene that codes for the KA1 subunit of the kainate-preferring glutamate receptor, and SLC6A4, the gene that codes for serotonin transporter, may help to predict treatment response in pediatric anxiety disorders.52,53 In the future, biosignatures (eg, a panel of genetic, neuroimaging, and/or physiologic biomarkers) may be used to guide individualized treatment recommendations. Given that 20% to 35% of youth treated with SRIs and CBT may not receive significant benefit from available current treatment interventions,8 it will be important

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to identify medications with novel mechanisms of action to our psychopharmacologic armamentarium. In this regard, studies of adults with anxiety spectrum disorders have observed increased central glutamate concentrations54,55 and glutamatergic hyperactivity is hypothesized to be implicated in the pathophysiology of anxiety disorders and is an emerging target of novel therapeutics being developed for the treatment of anxiety disorders.56,57 Thus, it will be important to evaluate glutamatergic modulators in youth with anxiety disorders such as D-cycloserine, memantine, and minocycline.58 Finally, some data implicate other neurochemical systems in youth with anxiety disorders, including clonidine-challenge studies, which suggest enhanced central adrenergic sensitivity in pediatric patients with anxiety disorders,59 raising the possibility that anti-adrenergics (eg, guanfacine, clonidine) may hold promise as treatments for anxious youth. However, despite some evidence, which suggests that these agents may be effective in treating anxiety disorders in adults,60 only singledose studies exist in anxious children and adolescents.61 REFERENCES

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