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DEPRESSION AND ANXIETY 29:328–339 (2012)

Review ESTABLISHING THE NEUROBIOLOGIC BASIS OF

TREATMENT IN CHILDREN AND ADOLESCENTS WITH GENERALIZED ANXIETY DISORDER

Jeffrey R. Strawn, M.D.,1,2∗ Anna M. Wehry,1 Melissa P. DelBello, M.D.,1,2 Moira A. Rynn, M.D.,3 and Stephen Strakowski, M.D.1

Generalized anxiety disorder (GAD) is associated with significant morbidity in children and adolescents, yet only recently have the neuropharmacology and neu- rophysiology of this condition been studied in youth. Accumulating data suggest structural and functional abnormalities within the brain’s fear networks in youth with GAD. Additionally, seven studies examined the efficacy of medications that modulate this system and, in some cases, the direct effects of these medications on structures within these networks (e.g. amygdala, ventrolateral prefrontal cor- tex [VLPFC]). In this review, we summarize the extant functional, functional connectivity, and structural neuroimaging data in children and adolescents with GAD. In addition, data concerning selective serotonin reuptake inhibitors (SS- RIs), selective serotonin norepinephrine reuptake inhibitors (SSNRIs), atypical anxiolytics, benzodiazepines, and psychotherapy are reviewed in the context of the neurophysiology of pediatric GAD. The existing data suggest abnormal ac- tivity within the amygdala, VLPFC, and anterior cingulate cortex, as well as the possibility of impaired connectivity among these brain regions. In addition to numerous cognitive behavioral therapy (CBT) trials, five randomized, controlled psychopharmacologic trials primarily in youth with GAD suggest that SSRIs and SSNRIs are effective for this condition. These findings also raise the possibility that functional activity within the amygdala and VLPFC may be altered follow- ing successful treatment. Depression and Anxiety 29:328–339, 2012. C© 2012 Wiley Periodicals, Inc.

Key words: GAD; fMRI; anxiety disorders; anterior limbic network; youth; SSRI

1Department of Psychiatry and Behavioral NeuroscienceUni- versity of Cincinnati, College of Medicine, Cincinnati, Ohio 2Cincinnati Children’s Hospital Medical Center, Department of Psychiatry, Cincinnati, Ohio 3Department of Psychiatry and New York State Psychiatric In- stitute (NYSPI), Columbia University, New York, New York

Disclosures: Dr. Strawn has received research support from Eli Lilly and Shire and from the American Academy of Child & Adoles- cent Psychiatry. Dr. DelBello has received research support from AstraZeneca, Eli Lilly, Johnson & Johnson, Shire, Janssen, Pfizer, Bristol-Myers Squibb, Repligen, Martek, Somerset, GlaxoSmithK- line, and Sumitomo; has participated in lecture bureaus for Bristol- Myers Squibb and Merck; and has consulted for GlaxoSmithKline, Eli Lilly, Merck, and Bristol-Myers Squibb. Dr. Rynn has received

research support from Eli Lilly and Shire. Dr. Strakowski reports research support from Eli Lilly, Janssen, AstraZeneca, Martek Bio- sciences, Nutrition 21, and Repligen; and has consulted for CME Outfitters, Adamed, Consensus Medical Communications (CME through the University of Minnesota; unrestricted grant from Ortho McNeil/Janssen) and Web MD. Ms. Wehry reports no biomedical conflicts of interest.

∗Correspondence to: Jeffrey R. Strawn, M.D., Dept. of Psychiatry, University of Cincinnati, Box 670559, Cincinnati, OH 45267-0559. E-mail: strawnjr@uc.edu

Received for publication 9 September 2011; Revised 29 November 2011; Accepted 4 December 2011

DOI 10.1002/da.21913 Published online in Wiley Online Library (wileyonlinelibrary.com).

Review: Pediatric GAD 329

INTRODUCTION Anxiety disorders .often first emerge during childhood and adolescence,[1, 2] cause significant difficulties in so- cial and family relationships and school performance,[3] and increase the risk of depressive and anxiety disor- ders later in life.[4] Moreover, pediatric anxiety disor- ders often co-occur with other psychiatric disorders, especially major depressive disorder.[1, 2] In addition, generalized anxiety disorder (GAD) is characterized by uncontrollable worry and excessive fear in multiple do- mains, and is one of the more common anxiety disor- ders. Youth with GAD are more likely to report suicidal ideation or to attempt suicide than healthy subjects, and are also more likely to report or attempt suicide than those with depression alone. These findings suggest that GAD increases the risk for suicidal ideation or suicide attempts in children and adolescents.[5, 6] Unfortunately, children and adolescents suffering from anxiety disorders are often not identified and frequently do not receive treatment.[7, 8]

Despite the prevalence and associated morbidity of GAD, only recently has the neurophysiology of GAD in adolescents been evaluated.[9] Specifically, recent stud- ies of adolescents with GAD suggest dysregulation of central fear circuitry[10] that includes components of the anterior limbic network (ALN) and involves con- nections between the amygdala and the ventromedial prefrontal cortex (Brodmann area [BA] 11), ventrolat- eral prefrontal cortex (VLPFC, BA 10/47) along with the rostral insula and subgenual and rostral anterior cin- gulate cortex (ACC; BA 25, BA 24/32).[11] The ALN is innervated by multiple systems whose neurochemistry has been implicated in anxiety disorders in adults. For ex- ample, serotonergic neurons, which originate from the median raphe nuclei,[12, 13] innervate many of the indi- vidual components of the ALN and these structures (e.g. amygdala, ACC, etc.) contain numerous serotonin (5- hydroxytryptamine, 5-HT) receptors. Importantly, the serotonergic system (i.e. raphe nuclei and its associated projections), which is functionally linked with the ALN, is often the direct target of psychopharmacologic in- terventions in both youth and adults with GAD (e.g. selective-serotonin reuptake inhibitors, SSRIs). Simi- larly, structures such as the amygdala and hippocampus are densely coated with receptors for the inhibitory neu- rotransmitter γ -amino-butyric acid (GABA) that serve as targets for anxiolytics such as benzodiazepines.[14] Over the last decade, important data have emerged regard- ing the neurophysiology of GAD in youth and the psy- chopharmacologic treatment of children and adolescents with GAD[15] and these parallel investigations now per- mit an integrated understanding of the neural bases of treatment in youth with GAD.

In this article, we review neuroanatomical and neu- rofunctional imaging studies in youth with GAD and synthesize these findings in order to develop a working neurobiological model of pediatric GAD that involves dysregulation within the central circuitry that subserves

Figure 1. The anterior limbic network (ALN). The ALN consists of the ventrolateral prefrontal cortex (green), which is shown in the top brain (dorsal view), and the anterior cingulate cor- tex (yellow) and the amygdala (red), which are depicted in the medial view (bottom). In addition, the dorsolateral prefrontal cortex (blue) is shown, although this region is not explicitly part of the ALN. Inhibitory relationships among these structures are reflected by dashed lines whereas sold lines represent excita- tory relationships. Gross brain photographs courtesy of Bruce Giffin, PhD.

emotional regulation and fear processing. In addition, we review evidence for neuropharmacolgic and psychother- apeutic interventions in pediatric GAD, and how these treatments may be targeting this dysfunctional neuro- circuitry.

THE ALN IN GAD Functional neuroimaging studies of adults with anx-

iety disorders have frequently implicated structures within the ALN (Fig. 1) including the amygdala, VLPFC, and the ACC.[16–18] The extant data concerning the neurobiology of GAD in adolescents suggest dys- function in the neural networks responsible for emo- tional processing. Among these networks, the ALN, consists of linked subcortical (limbic) and cortical (me- dial orbitofrontal and ventrolateral prefrontal) regions which share common phylogenetic and cytoarchitectural features.[19] Reciprocal connections of this network with dorsal prefrontal areas contribute to the cognitive ex- pression of mood whereas abundant connections and outputs of the prefrontal regions of the ALN constantly monitor both internal and external sensory information in order to modulate emotional and social behavior and, ultimately, maintain emotional homeostasis.[19, 20] In ad- dition, the ACC appears to play an important regulatory function within this network[21] by integrating cogni- tive and emotional functions that are subserved by this network.[11] Below, each specific component of the ALN

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330 Strawn et al.

will be reviewed with regard to specific structural and functional findings in pediatric patients with GAD.

AMYGDALA The amygdala resides deep within the limbic system

and is principally responsible for generating the central fear response. This bilateral structure is composed of multiple nuclei that are reciprocally connected to the hypothalamus, hippocampus, and neocortex. In addi- tion, two major efferent projections (stria terminalis and ventral amygdalafugal pathways) originate from the amygdala. The stria terminalis innervates the nucleus accumbens and the hypothalamus, whereas the ventral amygdalofugal pathyway innervates the medial thalamus and rostral ACC.

Structural neuroanatomic studies of amygdala in youth with GAD have produced inconsistent results. For example,De Bellis et al.[22] noted that in GAD youth, amygdala volumes were increased compared to healthy subjects, whereas a subsequent study using voxel-based morphometry observed decreased left amygdala volumes in adolescents with anxiety disorders (GAD: n = 13, to- tal n = 17) compared to healthy subjects.[23] Increased gray and white matter volumes of the superior tempo- ral gyrus (STG)—a region which is dense with afferent projections from the amygdala—have been observed in youth with GAD[22] as well. This latter finding is of par- ticular interest in that the STG is likely responsible for higher cognitive processing of fear and may therefore modulate amygdala activity.

In addition to potential structural differences in youth with GAD, eight functional magnetic resonance imaging (fMRI) studies demonstrated increased amygdala activa- tion in response to a variety of emotional probes. Specif- ically, in unmedicated adolescents with GAD, right amygdala activation was increased in response to an- gry faces[24] and bilateral activation of this structure occurred in response to fearful faces.[2] These find- ings of increased amygdala activation in youth with GAD are consistently observed with multiple fMRI tasks (Table 1); however, some tasks have generated bilateral amygdala responses, whereas in other tasks, laterality has been observed. Specifically, right amygdala activa- tion has been observed when adolescents with GAD view fearful faces [McClure et al., 2006b]. In contrast, bilat- eral amygdala activation was observed when probe de- tection tasks, which include paired affective faces, were used.[2, 24]

With regard to the coordinated activation of the amygdala and other components of the ALN in youth with GAD, a recent investigation observed that acti- vation of the amygdala, ventral prefrontal cortex, and ACC cross-correlated more extensively in adolescents with GAD (n = 15) who were viewing fearful faces as compared to healthy subjects (n = 20) [McClure et al., 2007]. Interestingly, in this study, when the attention state of the adolescents involved a focus on subjectively experienced fear, increased activation of the ACC was

observed [McClure et al., 2007]. With regard to the cross correlation of amygdala–ACC–VLPFC activation described above, Monk and colleagues (2008)[25] also noted that in adolescents with GAD, less “negative cou- pling” between the VLPFC and amygdala occurred; this finding suggested a failure of either modulatory or com- pensatory functions of the VLPFC. Similarly, the corre- lation of right amygdala activation (in response to angry faces) with activation of the right VLPFC appeared to be weaker in adolescents with GAD as compared to healthy subjects.[24]

VENTROLATERAL PREFRONTAL CORTEX (VLPFC)

The VLPFC, which includes Broadmann areas 44, 45, and the lateral portion of 46 (Fig. 1), serves a number of regulatory functions, including modulating amygdala activity[24] and, in some cases, responds in tandem with amygdala to emotional probes.[26] In addition, VLPFC subserves voluntary aspects of affect regulation[27] and, in lower mammals, may be involved in extinction pro- cess in certain fear conditioning tasks,[28] which is of significance given that fear learning is fundamentally impaired in GAD [see [29] for detailed review]. Conse- quently, it is also not surprising that this region is repeat- edly implicated in fMRI studies of adolescents with GAD (Table 1).

There have been few structural neuroimaging stud- ies of the VLPFC in pediatric anxiety disorders (Ta- ble 2). However, one recent study evaluated 17 patients with anxiety disorders (13 patients with GAD, mean age 12.4 + 2.2 years) and 34 healthy, comparison subjects (mean age 12.4 + 2.2) and, using voxel-based morphom- etry, observed decreased gray matter volumes of the VLPFC bilaterally in youth with anxiety disorders.[23] To date, three fMRI studies also suggest increased acti- vation of VLPFC in adolescents with GAD [25, McClure et al., 2006; Strawn et al., 2009] (Table 1). Interestingly, these activations appeared to be present when adoles- cents viewed aversive affects, including fearful faces and angry faces, suggesting a coordinated role of this region in response to threat. For example, when adolescents with GAD viewed angry faces, Monk and colleagues[25] observed increased activation in this region relative to healthy subjects, and found that the severity of the anx- iety symptoms was inversely related with right VLPFC activation. Taken together, these findings suggest that activation within the VLPFC might represent a compen- satory response to excessive amygdala activation in youth with GAD. This idea is further supported by the finding of [30] that successful treatment with the SSRI, fluox- etine, or cognitive-behavioral therapy (CBT) increases activity within this region in adolescents with GAD.

McClure et al. (2006b) found that VLPFC activity correlated with amygdala and ACC activation in youth with GAD. Also, increased connectivity was observed between the right VLPFC and amygdala in youth with GAD in addition to negative connectivity between the

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Review: Pediatric GAD 331

TABLE 1. Functional magnetic resonance imaging (fMRI) and functional connectivity (Fc) studies of pediatric generalized anxiety disorder (GAD)

Anterior cingulate Ventrolateral

prefrontal Reference fMRI task cortex (ACC) cortex (VLPFC) Amygdala Other

Thomas et al., 2001

Passive viewing of fearful and neutral faces

fMRI: ↑ R amygdala activation in response to fearful faces

Killgore and Yurallun-Todd, 2005

Passive viewing of fearful and neutral faces

fMRI: ↑ bilateral activation in response to fearful faces

[2] Passive viewing of affective faces

fMRI: ↑ activation in response to fearful faces

fMRI: ↑ activation of orbitofrontal cortex in response to fearful faces.

[25] Probe detection task utilizing facial affect recognition

fMRI: ↑ RVLPFC activation during viewing of angry faces that inversely correlates with the severity of anxiety symptoms

McClure et al., 2006a

Passive viewing of affective faces

fMRI: ↑ R amygdala pre-treatment activation in response to fearful faces correlates with tx response (CBT + SSRI)

McClure et al., 2006b

Passive viewing of affective faces

fMRI: ↑ activation during viewing of fearful faces Fc: ACC correlates with ACC and VLPFC activation

fMRI: ↑ activation during viewing of fearful faces Fc: VLPFC correlates with amygdala and ACC activation

fMRI: ↑ R amygdala activation during viewing of fearful faces. Fc: Amygdala activation correlates with ACC and VLPFC

McClure et al., 2007a

Face-attention paradigm with fearful, happy, neutral, and angry faces

fMRI: > L amygdala activation (during afraid–fear versus afraid–happy contrasts) predicted posttreatment improvement following CBT or fluoxetine

[24] Probe detection task utilizing facial affect recognition with paired faces (angry/neutral and happy/neutral, neutral/neutral)

fMRI: ↑ R amygdala activation during viewing of angry faces correlates with the severity of anxiety symptoms. Fc: ↑ RVLPFC connectivity with R amygdala and R amygdala exhibits negative connectivity with the R VLPFC

[30] Probe detection task utilizing facial affect recognition

fMRI: Treatment- associated ↑ in R VLPFC activation during viewing of fearful faces, following CBT or fluoxetine.

fMRI: ↑ bilateral activation during viewing of fearful faces following treatment with CBT

aIn this study, 75% of adolescents met criteria for GAD.

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332 Strawn et al.

TABLE 2. Structural MRI studies of pediatric generalized anxiety disorder (GAD)

Ventrolateral prefrontal Reference cortex (VLPFC) Amygdala Other

[22] ↑ superior temporal gray (STG) matter volumes in youth with GAD; correlation between anxiety sx and STG gray matter

[65] ↑ R and total amygdalar volumes in GAD patients

No differences between GAD patients and healthy comparison subjects in cerebral gray and white matter, temporal lobe, hippocampal, and basal ganglia volumes and measures of the midsagittal area of the corpus callosum

[23]a Subthreshold decreases in gray matter volume of bilateral VLPFC

↓ L and total amygdalar gray matter volume in youth with anxiety disorders

Subthreshold decreases in gray matter volume of the precuneus

aIn this study, 13 of 17 subjects met criteria for GAD, nine for social phobia, and three for separation anxiety disorder.

Figure 2. The anatomy of the anterior cingulate cortex (ACC). The ACC is subdivided into a series of subregions, including the subgenual ACC (sgACC, blue), the perigenual ACC (pgACC, green), the anterior dorsal ACC (adACC, red) and the posterior dorsal ACC (pdACC, yellow). Gross brain photograph courtesy of Bruce Giffin, PhD.

right amygdala and right VLPFC.[24] A recent study of adolescents with GAD (n = 10) that used right VLPFC as a seed region, found increased connectivity between this region and the medial prefrontal cortex; the latter region is responsible for interoception (i.e. sensitivity to stimuli arising from the body).[31] This finding suggests altered regulation of brain regions subserving the processing of past emotional associations and events and responsible for interpreting the self-relevance of emotional stimuli in young people with GAD.

ANTERIOR CINGULATE CORTEX (ACC) The cingulate cortex forms the superior boundary of

the limbic system and overlies the corpus callosum from the rostrum to the splenium.[32] Neurons within the ACC project to motor systems and to amygdala, peri- aqueductal gray matter, hypothalamus, and autonomic brainstem motor nuclei.[32] Moreover, the ACC can be divided into a series of subregions (Fig. 2) that exhibit both differential connectivity to specific limbic compo- nents and also subserve a diversity of functions from re-

ward, cognition, and emotion to motivation and motor control [for review see [33, 34]]. Perhaps the most impor- tant functions of the ACC are the dual processing of cognitive and emotional information as well as the func- tional integration of these two streams.[11, 21]

To date, there are no structural studies of the ACC in children and adults with GAD; however, fMRI studies of this region in youth with GAD have revealed increased activation of this region during the viewing of fearful faces [McClure et al., 2006b. Moreover, ACC activation correlates with amygdala and VLPFC activation in youth with GAD [McClure et al., 2006b].

In addition, a recent study of 16 adolescents with GAD and/or social phobia evaluated intolerance-of- uncertainty, a trait marker of anxiety, and found greater activity in orbitofrontal cortex and left amyg- dala and also increased activation in the subgenual ACC in those adolescents who had higher intolerance- of-uncertainty as compared to healthy subjects and youth with GAD/social phobia who had low ratings for intolerance-of-uncertainty.[35] These findings sug- gested that even within a phenotypically homogenous group of pediatric patients, significantly different patho- physiological and affective responses may occur and these responses might be linked to trait measures (e.g. intolerance-of-uncertainty) that might be one risk fac- tor or endophenotype for GAD and other anxiety disorders.[35]

NEUROPHARMACOLOGY OF PEDIATRIC GAD

Only within the last decade have psychopharmaco- logic studies of youth with anxiety disorders (other than obsessive-compulsive disorder, OCD) focused on spe- cific anxiety disorders (e.g. GAD, social phobia, etc). All randomized, controlled trials of SSRIs, SSNRIs, benzo- diazepines, and other agents (e.g. buspirone), in which ≥50% of patients were diagnosed with GAD, are re- viewed.

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Review: Pediatric GAD 333

SERTRALINE Sertraline was among the first SSRIs to be evalu-

ated for the treatment of youth with GAD in a pilot, randomized, placebo-controlled trial.[36] Children and adolescents, aged 5–17 years (n = 22), were treated for 9 weeks with fixed-dose sertraline (50 mg/day). Com- pared with placebo-treated youth, significant improve- ment was noted in the sertraline-treated patients on the Hamilton Anxiety Rating Scale (HAM-A,[37] Clinical Global Impression—Severity (CGI-S; 1 = not mentally ill to 7 = severely ill) and—Improvement (CGI-I; 1 = very much improved to 7 = very much worse) scores. Additionally, the authors of this study controlled for the severity of cooccurring depressive symptoms and ob- served a highly significant “main treatment effect for anxiety,” but not for depression.[36] No differences in side effects were observed between the sertraline-treated patients and those who received placebo.

Recently, the Child/Adolescent Anxiety Multimodal Treatment Study (CAMS) evaluated the comparative ef- ficacy of sertraline, CBT, or the combination of sertra- line + CBT (COMB) in patients aged 7–17 years (mean age = 11.8 years) with social phobia, separation anxiety disorder, GAD, or any combination of these anxiety dis- orders [Walkup et al., 2008]. Sertraline was initiated at 25 mg daily and was titrated to 200 mg daily (mean dose 146 ± 61 mg/day, range 25–200 mg/day). 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 [Walkup et al., 2008]. In addition, sertraline was well tolerated as rates of

adverse events were similar to placebo. However, those children who were receiving CBT were less likely to re- port insomnia, fatigue, sedation, restlessness, or fidget- ing than those who received sertraline [Walkup et al., 2008].

FLUOXETINE Birmaher and colleagues[38] evaluated the efficacy

and tolerability of fluoxetine in a randomized, placebo- controlled trial of youth with GAD, separation anxiety disorder, and social phobia (mean age 11.6 ± 3 years, range 7–17 years). In this 12-week trial, 60% of placebo- treated youth met criteria for GAD, whereas 68% of those who received fluoxetine met criteria for GAD. Flu- oxetine was initiated at 10 mg daily and was titrated to 20 mg daily at the end of the first week and was gen- erally well tolerated with 76% of patients completing the trial (84% placebo completion, p = .39). Compared to placebo, statistically significant improvements were noted in the fluoxetine-treated patients on the Screen for Anxiety-Related Emotional Disorders (SCARED, both child and parent versions) scores, Pediatric Anxiety Rat- ing Scale (PARS) score,[39] CGI-I, CGI-S and CGAS (Table 3). Rates of CGI-I scale response were signifi- cantly higher in the fluoxetine group than in the placebo group and treatment effects.

VENLAFAXINE The selective serotonin norepinephrine reuptake

inhibitor, venlafaxine extended-release (ER) was re- cently evaluated in two randomized, 8-week, fixed-dose,

TABLE 3. Randomized placebo-controlled trials in pediatric generalized anxiety disorder (GAD)

Dose range Average Effect Baseline Endpoint Reference Duration Treatment N (mg/day) dose size symptoms score symptom score

Walkup et al., 2008 12 weeks (PARS) (PARS) Sertraline 133 25–200 146.0 ± 60.8 mg 0.2 18.8 ± 3.9 9.8 ± 6.2 CBT 139 - 0.1 18.9 ± 3.9 10.8 ± 5.4 Combination 140 25–200 133.7 ± 59.8 mg 0.4 19.4 ± 3.9 7.4 ± 6.0 Placebo 76 50–200 175.8 ± 43.7 mg 19.6 ± 3.9 12.6 ± 6.3

[36] 9 weeks (HAM-A) (HAM-A) Sertraline 11 25 (Week 1) Fixed dose 0.7 20.6 ± 3.6 7.8 ± 5.7 Placebo 11 50 (Week 2–9) Fixed dose 23.3 ± 4.0 21.0 ± 7.8

[40] 8 weeks Study 1: Venlafaxine ER 76 37.5–225 Placebo 77 Study 2: 78 37.5–225 Venlafaxine ER Placebo 82

[38] 12 weeks (PARS) (PARS) Fluoxetine 37 10 (Week 1) Fixed dose 0.2 15.6 ± 3.5 7.1 ± 5.9 Placebo 37 20 (Week 2-12) Fixed dose 14.9 ± 3.5 9.3 ± 4.8

[41] 8 weeks (PARS) (PARS) Fluvoxamine 61 2.9 ± 1.3 mg/kg 0.5 18.7 ± 2.9 9.0 ± 7.0 Placebo 63 3.8 ± 1.7 mg/kg 19.0 ± 3.0 15.9 ± 5.3

BMS, 2010 8 weeks Buspirone placebo 15–60 Unreported N/A

PARS, Pediatric Anxiety Rating Scale; HAM-A, Hamilton Anxiety Rating Scale aIn this study, 75% of adolescents met criteria for GAD.

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334 Strawn et al.

placebo-controlled trials youth with GAD, aged 6–17 years (n = 323).[40] Extended-release venlafaxine (ER) was initiated at 37.5 mg daily in all participants. For youth weighing between 25 and 39 kg, the highest dose allowed was 112.5 mg daily, and for patients weighing between 40 kg and greater, it was 225 mg daily. In this re- port, which includes data from two identically designed studies (Study 1 and Study 2), venlafaxine ER was supe- rior to placebo in producing improvements in scores on the GAD section of the Columbia K-SADS as well as PARS, HAM-A, and SCARED (parent and child) scores only in Study 1 (p < .001) and in Study 2 (p < .06). In the pooled analysis of Study 1 and Study 2, venlafaxine ER as compared to placebo demonstrated statistically significant differences for improving anxiety symptoms (p < .001) and had a higher response rate (69% vs. 48%; p < .04).[40] Children and adolescents who received ven- lafaxine were more likely to experience asthenia, pain, anorexia, and somnolence as well as weight loss com- pared with those receiving placebo.

FLUVOXAMINE Fluvoxamine, a potent SSRI, has been evaluated in

youth with anxiety disorders including separation anxi- ety disorder, social phobia, and GAD.[41] One hundred twenty-eight children with anxiety disorder (51% with GAD) were randomized to fluvoxamine or placebo for an 8-week study. Fluvoxamine was flexibly titrated to 300 mg daily (mean dose 2.9 + 1.3 mg/kg) and sig- nificant differences were found in CGI-I and endpoint PARS scores (p < .001). In addition, fluvoxamine was well tolerated with only abdominal discomfort and in- creased motor activity occurring more frequently in the fluvoxamine-treated youth than in those who received placebo.[41]

BUSPIRONE To date, two open-label studies have evaluated the

efficacy and tolerability of the 5-HT1A agonist bus- pirone in youth with overanxious disorder (now defined as DSM-IV-TR GAD). Kutcher and colleagues [1992] reported that over 6 weeks of treatment with flexibly dosed buspirone (15–30 mg/day), anxiety significantly improved in youth with overanxious disorder. Subse- quently, Simeon [1993] reported that in a sample of 13 children and adolescents (nine of whom had primary or secondary diagnoses of overanxious disorder), anxiety symptoms significantly improved over 4 weeks of treat- ment. In addition, buspirone was generally noted to be well tolerated although some patients experienced se- dation, nausea, stomachaches, and headaches [Simeon, 1993]. Two randomized, placebo-controlled trials of buspirone have examined the efficacy and tolerability of this agent in pediatric patients (age range: 6 to 17 years of age, n = 559). In these studies that utilized 15–60 mg of buspirone per day, no significant differences between buspirone and placebo were noted for GAD symptoms [BMS, 2010]. In addition, pharmacokinetic studies of

this agent revealed plasma exposure to buspirone (and its active metabolite, 1-(2-pyrimidinyl)-piperazine, [1-PP]) were equivalent or greater in pediatric patients than in adults.[42]

BENZODIAZEPINES Despite the common use of benzodiazepines for the

adjunctive treatment of GAD in adults, the results of trials of this class of medication in youth with GAD or overanxious disorder have been mixed. Twelve youth with overanxious disorder (DSM-III-R criteria) who re- ceived open-label alprazolam (0.5–1.5 mg/day) over 4 weeks were significantly improved in terms of anxiety symptoms and insomnia. Moreover, in this study, alpra- zolam was generally well tolerated, despite some seda- tion, agitation, headaches, and nausea.[43] A subsequent double-blind, placebo-controlled trial of alprazolam in youth aged 9–16 years (n = 12) with overanxious disor- der (DSM-III-R criteria) found improvement in global ratings, but this finding failed to reach the level of sta- tistical significance, which might be related to this study being significantly underpowered. Alprazolam was well tolerated with some reports of fatigue and dry mouth and there were no reports of withdrawal symptoms.[44] To our knowledge, there are no double-blind, placebo- controlled trials of benzodiazepines in pediatric patients with GAD.

PSYCHOTHERAPEUTIC INTERVENTIONS FOR

PEDIATRIC GAD Over the last two decades, substantial advances have

been made in the psychotherapeutic treatment of youth with anxiety disorders. Of the available studies of psychotherapy, most have evaluated the efficacy of CBT[45, 46,47, 48] although, several alternate forms of psy- chotherapy that are efficacious in other types of psy- chopathology in youth remain understudied in youth with GAD (e.g. interpersonal psychotherapy for adoles- cents (IPT-A), mentalization-based therapy, etc.). In one study of IPT-A for depressed adolescents, a subsample diagnosed with comorbid GAD 85% (11 out of 13) were no longer positive for the presence of GAD. These pre- liminary data suggest that ITP-A may have some ben- eficial effects for adolescent GAD.[49] With regard to CBT, a Cochrane Review of 13 studies of childhood anxiety disorders found that, for youth with mild-to- moderate anxiety (498 subjects and 311 controls), CBT was superior to wait list or attention control.[48] In this report, response rates for remission of any anxiety di- agnosis was 56% for CBT versus 28.2% for controls treatments (NNT = 3).[48] Importantly this analysis also suggested that individual, group, and family/parental formats of CBT resulted in similar outcomes.[48] To date, the largest study to evaluate the efficacy of CBT in anxious youth is CAMS, which evaluated the compar- ative efficacy of sertraline, CBT, or COMB in patients

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Review: Pediatric GAD 335

aged 7–17 years with social phobia, separation anxiety disorder, GAD, or any combination of these three anx- iety disorders (as discussed previously and see Table 4) [Walkup et al., 2008]. CBT was effective and well toler- ated in reducing symptoms of anxiety in all subjects dur- ing the 12-week trial [Table 1]. However, only recently has a preliminary analyses of those youth with GAD only (n = 33) been reported.[50] In this analysis, clinical severity ratings (CSRs) were reduced by 3.2 points when GAD patients were treated with COMB, whereas CSRs were reduced by 3.13 points when patients were treated with sertraline only and finally CBT alone resulted in CSR reductions of 2.8 (compared to a CSR reduction of 0.25 when treated with placebo).[50] Finally, one study retrospectively evaluated the efficacy of intensive and nonintensive psychodynamic psychotherapy in youth with overanxious disorder.[51] In this study, intensive psychotherapy produced superior outcomes for youth with overanxious disorder as compared to once weekly therapy and importantly, this difference in outcome was not observed in other anxiety disorders (e.g. OCD, sep- aration anxiety disorder, or simple phobia).[51]

EFFECTS OF PSYCHOPHARMACOLOGIC AND PSYCHOTHERAPEUTIC INTERVENTIONS ON ALN NEUROCIRCUITRY

Having described the functional neurocircuitry of GAD in youth and having reviewed the available ev- idence for pharmacologic and psychotherapeutic treat- ments of GAD in children and adolescents, the extant lit- erature regarding treatment effects on the ALN in GAD will be discussed in detail. However, given that only a limited number of studies have directly evaluated the di- rect effects of these treatments on the neurocircuitry of GAD in youth, we have augmented this section by in- cluding a review of the existing literature of treatment- related neurophysiologic changes in adults with GAD.

Recently, the direct effects of psychopharmacologic and psychotherapeutic treatment on ALN neurocir- cuitry in youth with GAD were examined.[30] In this study of 14 youth with GAD treatment, flexibly dosed fluoxetine (5–40 mg/day) and treatment with CBT were both associated with increased activation of the right VLPFC in response to pictures of angry faces.[30] Ad- ditionally, there has been a previous study evaluating the predictive value of regional activity within the ALN in youth with anxiety disorders who were treated with fluoxetine and CBT.[52] In this study, lower left amyg- dala activation predicted posttreatment improvement, regardless of whether the children or adolescents were treated with CBT or fluoxetine.[52]

At least four studies have evaluated the effects of SSRIs and SSNRIs on ALN circuitry in adults with GAD and, in some cases, in healthy adults. To this end, administration of the SSRI, citalopram, and its s- enantiomer, escitalopram, both attenuate right amygdala responses to aversive faces[53;54] and reduce activation within the parahippocampal cortex to emotionally signif-

icant stimuli.[55] Among the SSNRIs, duloxetine admin- istration (60 mg daily for 2 weeks) to healthy volunteers results in decreased activation of the amygdala, anterior insula, and ventral ACC and was associated with en- hancement of functional coupling between the amygdala and the anterior insula, suggesting that “duloxetine at- tenuates the bottom-up processing of biologically salient information in extended amygdala circuitry, while at the same time possibly potentiate[s] the effective communi- cation between its subparts.”[56] Additionally, in adults with GAD, in whom bilateral amygdala activity is in- creased at baseline, clinical response to open-label ven- lafaxine for 8 weeks is predicted by pretreatment ACC activity[57] and by rostral ACC–amygdala activity.[58]

Lastly, at least three studies in adults have evaluated the effects of benzodiazepines in ALN neurocircuitry. For example, oral administration of the benzodiazepine, lorazepam blunts bilateral amygdala activation in re- sponses to aversive facial stimuli in healthy adults.[16, 59] Furthermore, in healthy adult volunteers, diazepam de- creases right amygdala and right orbitofrontal cortex activation and accentuates right ACC activation in re- sponse to fearful faces.[60]

DISCUSSION Over the last decade, parallel lines of research have

supported the efficacy of SSRIs, SSNRIs, and CBT in the treatment of pediatric GAD and have also illus- trated complex dysregulation within the ALN. However, recently these distinct lines of research have begun to converge as studies have attempted to integrate the clin- ical effects of successful treatment with SSRIs and psy- chotherapy with the accompanying changes in the un- derlying neurophysiology of GAD. Taken together, this work suggests that SSRIs and CBT may not only mod- ulate the activity of specific structures within the ALN, but that functional responses of ALN structures to emo- tional probes could predict treatment outcome.

Certainly, the extant data further highlight the need for integration among future psychopharmacologic and neuroimaging studies in youth with GAD. Specif- ically, these studies could enable experimental ma- nipulations of specific neurocognitive features (e.g. attention, threat bias, etc.) to elucidate novel therapeu- tic approaches that are capable of modifying specific functions within neurocircuitry (e.g. the ALN) and may be performed in parallel with measures of environmen- tal events (e.g. exposure to significant early separation events, parental overprotection), genotypes (e.g. 5-HT transporter polymorphisms)[61] and temperament.[62] In addition, it will be critical to understand the neuro- physiologic targets of psychotherapies (including CBT, IPT-A, and psychodynamic psychotherapy) as well as for medications from other and novel classes on the func- tional activity within the ALN. Further, we anticipate that psychotherapeutic strategies for youth with GAD could potentially be linked with our emerging under- standing of the neurophysiology of pediatric GAD. As

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an example, accumulating data suggest increased threat bias in adolescents with GAD compared to healthy com- parison subjects[63] and that in adolescents with GAD who are attending to threat, attentional bias may mod- ulate the activity of the VLPFC [McClure et al., 2007]. Thus, therapies aimed at correcting attentional bias may promise both efficacy and the exciting possibility of an fMRI biomarker of either treatment response.[29] Also, pre- and posttreatment studies in youth with GAD are urgently needed to predict which patients might re- spond to specific classes of medications or modalities of psychotherapy. Given that response to specific medica- tions and psychotherapies may be moderated by unique individual neurocognitive or neurophysiologic profiles, identifying neurophysiologic signatures of specific traits within youth with GAD (e.g. intolerance of uncertainty) will be an important aspect of future studies.

Several important caveats exist regarding the interpre- tation of reports of the neurocircuitry of pediatric GAD. Specifically, the existing literature points to abnormali- ties within central “fear circuits” (including the ALN) in conditions other than GAD, including other anxi- ety disorders and major depressive disorder. To date, neuroimaging investigations have generally examined depressed youth[64] or anxious youth [McClure et al., 2007;2, 24], independently. Yet, accumulating evidence suggests that the neural circuitry known to subsume the processing of fear, a cardinal feature of anxiety dis- orders, is hyperresponsive to threat perception and/or lacks a modulatory capacity, in both adolescents with major depressive disorder and anxiety disorders [Mc- Clure et al., 2007]. Thus, because most prior investi- gations have assessed depressed and anxious youth sepa- rately, the neurophysiologic impact of cooccurring affec- tive symptoms on these circuits in adolescents with GAD remains unclear. Clarifying the neurophysiological differences between anxious and depression (e.g. comor- bid GAD and MDD), particularly with regard to differ- ences in emotional processing, may lead to more effec- tive treatment strategies, thereby improving outcomes for individuals with GAD and cooccurring major depres- sive disorder. These neurophysiologic differences could serve as biomarkers for distinct clinical presentations, which are known to have differing prognoses and dif- fering responsiveness to novel treatments in youth. An- other limitation of the existing neurophysiologic inves- tigations undertaken to date is that development influ- ences are poorly understood. This is to say that the avail- able studies have examined “adolescents” or “adults,” and this approach does not permit examination of the neuroanatomic and neurophyiologic shifts which likely occur as continuous processes across development. To this end, some of these studies suggest differences in the pathophysiology of these conditions in youth and adults, yet the degree to which these findings reflect (1) ongoing neurodevelopmental processes, (2) shifts in neurophys- iologic processes, (3) differences between the adult and child “forms” of GAD, or (4) evolution of the disorder remains to be determined. Finally, some of the processes

examined in fMRI tasks may also differ in pediatric GAD as compared to GAD in adults, leading to differing find- ings in adults. For example, many pediatric GAD studies have utilized tasks that involve threat bias and other in- dices of emotional processing[24, 25] whereas some recent work in adults with GAD suggests that “emotional pro- cessing avoidance” might be a key feature of GAD in the adult population [Newman et al., 2011].

The path from an initial understanding of the neurobi- ological effects of psychopharmacologic and psychother- apeutic treatments to the identification neurophysio- logic markers of treatment response (as well moderators or predictors of treatment response) contains many chal- lenges. First, the influence of comorbid affective symp- toms (e.g. depressive symptoms) will need to be better understood; although, some neuroimaging work in ado- lescents suggests that the neurophysiology of GAD as compared to other anxiety disorders and depressive dis- orders may be distinct.[2, 26] Specifically, comorbid con- ditions that are frequently present in children and ado- lescents with GAD share genetic, environmental, and behavioral risk factors;[1, 2] as such, the presence of these conditions will need to be included as a covariate in fu- ture studies. In addition, some of the neurophysiologic abnormalities described in adolescents with GAD exist in other pediatric anxiety disorders and in mood disorders. Thus, future studies must evaluate differences between adolescents with GAD and healthy comparison subjects and will need to elucidate between GAD and those with conditions that commonly cooccur with GAD (e.g. ma- jor depressive disorder, social phobia, separation anxiety disorder, etc.). Finally, the use of within-subject, longitu- dinal functional neuroimaging studies as well as the use of magnetic resonance spectroscopy studies of key re- gions within the ALN will be essential as we search for neurobiologic markers of treatment response and remis- sion in adolescents.

CONCLUSION In children and adolescents with GAD, the current

evidence suggests efficacy of the SSRIs (i.e. sertraline, fluvoxamine, and fluoxetine) and the SSNRI, venlafax- ine, but not the 5-HT1A partial agonist, buspirone. In addition, the available data are mixed with regard to the use of benzodiazepines in youth with GAD. Importantly, several lines of evidence suggest that psychopharmaco- logic interventions in youth may directly affect the func- tional neurocircuitry of GAD, particularly with regard to the ALN. Specifically, (1) the ALN is heavily innervated by serotonergic fibers and this system is directly affected by the SSRIs; (2) extensive populations of GABA recep- tors (the targets of benzodiazepines) are known to exist within the ALN and in particular; (3) SSRIs increase the activity of the VLPFC in youth; and (4) ACC ac- tivity predicts treatment response in youth with GAD. In addition, the extant literature supports the efficacy of CBT in youth with GAD (and mixed anxiety disorders) which can be administered in group-, individual-, and

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family-based settings. Additional studies that integrate psychopharmacologic and psychotherapeutic interven- tions with evaluations of the functional neurocircuitry in youth with GAD are urgently needed both to better understand the pathophysiology of this condition and to identify predictors of treatment response in order to decrease the morbidity and mortality of pediatric GAD.

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