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PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 439 P h a r m a c o l o g i c a l a s p e c t s Pharmacotherapy for anxiety disorders in children and adolescents Ian Kodish, MD, PhD; Carol Rockhill, MD, PhD; Chris Varley, MD Introduction A nxiety is a normal response to environmental stressors, and promotes safety by facilitating behavioral avoidance of threatening stimuli. This sense of threat is modulated by fear circuitry, including amygdala, hip- pocampus, and prefrontal regions. Anxiety disorders are thought to involve alterations in fear responsivity, driven Anxiety disorders are the most common mental health by adjustments in the tuning of specific circuit compo- diagnoses in youth, and carry risks for ongoing impair- nents, including deficiencies in the dampening of amyg- ments and subsequent development of other psychiatric dala stress responses by prefrontal regions.1The neuronal comorbidities into adulthood. This article discusses con- circuitry involved in the regulation of anxiety operates siderations for assessment and treatment of anxiety dis- within a context of environmental cues and across a orders in youth, with a focus on the evidence base of developmental landscape, such that assessment of nor- pharmacologic treatment and important clinical consid- mal developmental tasks and environmental stressors are erations to optimize care. We then briefly describe the essential for clinical evaluation. The distress associated impact of anxiety on neuronal elements of fear circuitry with clinical anxiety often elicits intense escape urges, to highlight how treatments may ameliorate impairments offering immediate symptom relief. This avoidance is so through enhanced plasticity. Overall, pharmacotherapy reinforcing that it may rapidly become habitual, resulting for anxiety disorders is effective in improving clinical symp- in increasingly impaired functioning. Treatment requires toms, particularly in combination with psychotherapy. reducing reinforcements associated with avoidance while Response is typically seen within several weeks, yet longi- gradually empowering youth to tolerate anxiety in the tudinal studies are limited. Selective serotonin reuptake face of potentially stressful challenges. inhibitors are thought to be relatively safe and effective Pharmacologic interventions may confer clinical benefit for acute treatment of several classes of anxiety disorders by reducing the degree of anxious reactivity, thereby in youth, with increasing evidence supporting the role of Author affiliations: Acting Assistant Professor, Department of Psychiatry neuronal plasticity in recovery. and Behavioral Sciences, University of Washington School of Medicine, © 2011, LLS SAS Dialogues Clin Neurosci.2011;13:439-452. Seattle, WA (Ian Kodish, Carol Rockhill); Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Keywords:anxiety disorder; pharmacotherapy; selective serotonin reuptake inhi- Medicine, Seattle, WA (Chris Varley) bitor; child; plasticity Address for correspondence:Ian Kodish, MD,PhD, Seattle Children’s Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105 USA (e-mail: [email protected]) Copyright © 2011 LLS SAS. All rights reserved 439 www.dialogues-cns.org PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 440 P h a r m a c o l o g i c a l a s p e c t s increasing the range of opportunities for children to optimum management of symptoms, yet excessive test- learn more adaptive responses to stressful stimuli. With ing or otherwise providing reinforcement of symptom successful treatment, extinction of recurrent anxiety emergence through heightened interventions is not rec- symptoms is thought to require neuronal plasticity to ommended. take effect, similar to other forms of learning. Selective serotonin uptake inhibitors (SSRIs) and other treatment Treatment of anxiety disorders modalities are thought to facilitate these neurochemical and neuroanatomical enhancements, contributing to A multimodal treatment approach, including a combi- clinical effectiveness.2This enhanced neuroplasticity may nation of medication, therapy, and environmental inter- also contribute to better response rates by augmenting ventions, is increasingly shown to confer greater other interventions such as psychotherapy. improvement in symptoms compared with unimodal treatments. Although the essential elements of success- Assessment and diagnosis of anxiety ful therapy are not clear, cognitive-behavioral therapy (CBT) studies have extensively demonstrated effective- Initial identification of anxiety disorders in children and ness in individual, group, and family formats.9 adolescents often occurs during medical visits to primary Randomized controlled trials (RCTs) of CBT have care providers. Presenting concerns typically include shown benefit for Generalized Anxiety Disorder avoidance of age-appropriate tasks, or excessive physical (GAD),10-14social anxiety disorder,10-14panic disorder,13 complaints such as headaches, dizziness, or stomachaches, obsessive–compulsive disorder (OCD),14-16and post-trau- which are particularly common presenting signs of anxi- matic stress disorder (PTSD).18These benefits have also ety at younger ages.3Physical complaints related to anx- been found to be maintained over time.19Therefore, for iety can be diverse,4and are often highly concerning to youth who meet criteria for anxiety disorders with mild- parents. A timeline of physical, psychological, and behav- to-moderate functional impairments, the American ioral symptoms, elicited from both the child and parents, Academy of Child and Adolescent Psychiatry recom- is valuable to assess the evolution of symptoms and con- mends psychoeducation for patients and their families sider exacerbating factors. A broad review focused on the and initially deferring use of medication to CBT.20 association between symptoms and psychosocial stress is However, for youth with moderate to severe anxiety also recommended, including past medical history and symptoms, multimodal treatment is recommended, family history of psychiatric illnesses and substance including medication in combination with CBT.21 abuse. General screening measures tailored to develop- Multiple RCTs support the efficacy of SSRIs, both alone mental level are available for providers to help identify and in combination with therapy, for the treatment of children with psychosocial difficulties,5and self-reports anxiety disorders in children and adolescents. may help to identify anxiety in children who are disin- Medication intervention may be started concurrently clined to reveal symptoms during examination.6 with psychotherapy, or may be initiated before starting therapy to reduce the impairing nature of severe symp- Medical evaluation toms and promote treatment effectiveness. Medication can also be added after engagement in CBT if initial psy- Despite the potential for physical symptoms to represent chotherapy does not provide satisfactory relief of symp- somatic complaints driven by anxiety, consideration of toms. It is important to recognize that both psychother- common medical issues related to anxiety disorders is apy and medication management result in improvement, essential.9,7Physical examination and judicious labora- but not necessarily in full remission of symptoms. tory testing targeting potential underlying relevant med- When considering pharmacologic agents, selection ical problems should be performed.8Common screens should be guided by the evidence base and clinical include tests for endocrine abnormalities (thyroid and guidelines, with special consideration for side-effect pro- fasting glucose), urine toxicology, respiratory problems, files and unique clinical characteristics to optimally tai- sleep abnormalities, cardiac conduction defects (partic- lor care. Informed consent is required from parents, and ularly if considering tricyclic agents), and seizure activ- when possible, from the child or adolescent. States vary ity. Pertinent findings can guide more specialized and in policies regarding obtaining consent or assent from 440 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 441 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 youth. Even if not required, direct discussion of med- The highest regarded clinical trial examining the impact ication use with the patient is likely to improve compli- of both manualized psychotherapy and medication on ance and engagement irrespective of age. symptoms of OCD in youth is the Pediatric OCD When initiating medications, frequent visits with the pre- Treatment Study (POTS). In this study, sertraline’s effec- scriber, typically every 2 to 4 weeks, are recommended tiveness in pediatric OCD for 12 weeks was compared to closely monitor for effectiveness and tolerance. with CBT, combined treatment, and placebo.13 Each Regular communication between the prescriber and the active treatment arm proved superior to placebo, and treating therapist is also encouraged. More frequent combined treatment was superior to either CBT or ser- provider contact is also recommended when there is a traline alone. Another RCT examining sertraline for history of depression, a strong familial preference, or youth with OCD also found significantly greater when compliance is a concern. Standardized rating scales improvement after active treatment compared with should be used to measure treatment effectiveness. After placebo,24 with lasting effects in 70% of patients who an effective dose of medication is reached, visit fre- were examined 12 months later.35 quency may be reduced. Even after symptom resolution, A 10-week RCT of pediatric outpatients with OCD cautious treatment calls for medication maintenance for showed fluvoxamine to be effective.27Despite the com- 1 year, followed by a gradual tapering off to allow obser- mon clinical finding that weeks of treatment with SSRIs vation of any recurrence of symptoms.22 are required prior to symptom response, improvements beyond placebo were evident by the first week and Evidence for effectiveness of showed gains through the course of treatment. SSRIs and SNRIs Other SSRIs with RCTs demonstrating effectiveness in the treatment of pediatric OCD include paroxetine28,29 A limited number of RCTs have evaluated antianxiety and fluoxetine.25,26Notably, fluoxetine treatment required agents in children and adolescents. To date, no medica- 8 weeks prior to showing effectiveness over placebo, and tions have been approved by the FDA for treatment of a higher dose only lengthened this response time. non-OCD anxiety in youth. Four medications have been Secondary analyses also showed that paroxetine demon- approved for OCD treatment in children and adoles- strated significantly lower response rates among youth cents. Medication and placebo response rates range with OCD and comorbid illness such as ADHD, tic dis- across studies, which are difficult to compare due to lim- orders, or oppositional defiant disorder (ODD).29 ited clinical samples and variability in measures of Overall, these clinical studies suggest a moderate treat- assessment and clinical response. Yet positive results ment effect that is relatively similar across SSRIs.23 have been demonstrated for multiple agents in the treat- Despite the much greater prevalence of non-OCD anx- ment of anxiety in both youth and adults, particularly iety disorders, studies are more limited in children and medications targeting serotonin reuptake. A meta-analy- adolescents. Furthermore, subtypes are often mixed sis of RCTs examining the tolerability and efficacy of within treatment arms, limiting the ability to compare pharmacotherapy for anxiety disorders in youth found response to treatment by specific disorder. Nevertheless, that SSRIs and SNRIs showed clear benefit with an RCTs of SSRIs have demonstrated efficacy in the treat- overall response rate almost double that of placebo.23 ment of GAD, separation anxiety disorder (SAD), and Regarding specific pediatric anxiety subtypes, OCD has social phobia, often in mixed populations with any one the largest number of positive RCTs, which reveal clin- or a combination of these (Table I). Although the data ical benefit after treatment with sertraline,15,24 fluoxe- are limited, the average likelihood of pharmacologic tine,25,26 fluvoxamine,27 or paroxetine.28,29 Evidence for treatment response for non-OCD disorders appears to citalopram is limited to open-label studies30-32and com- be slightly greater than for OCD.23 parison with fluoxetine without placebo.33 SSRIs are The largest RCT of non-OCD anxiety disorders to date first-line therapy for pharmacologic management of anx- is the Childhood Anxiety Multimodal Study (CAMS), iety disorders in youth, and three of the four medications which evaluated treatment of SAD, GAD, and social approved by the FDA for treatment of OCD in children phobia.36Treatment groups included sertraline only, CBT and adolescents are SSRIs: sertraline (≥6), fluoxetine only,37 combination treatment, or placebo. All three (≥7), and fluvoxamine (≥8).3 active treatments were superior to placebo (24%), with 441 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 442 P h a r m a c o l o g i c a l a s p e c t s the highest response in the combined condition. These initial fluvoxamine treatment still exhibited a high rate findings again suggest that, while monotherapy with of response to a subsequent open-label trial of fluoxe- either medication or psychotherapy alone can be effec- tine, supporting the clinical benefit of a subsequent trial tive for treating anxiety disorders, a multimodal using alternative SSRIs despite an initial lack of approach is more likely to be successful. This method is response to one agent. also thought to apply to pediatric depression38and com- Fewer studies have examined selective cohorts with plex forms of ADHD,39while evidence for combination diagnoses of specific non-OCD anxiety disorders. An therapy is limited for youth with PTSD.40,41 RCT examining paroxetine treatment in youth specifi- Other agents with demonstrated efficacy for youth with cally with social anxiety showed efficacy over placebo.35 non-OCD anxiety include fluvoxamine42,43and fluoxe- In addition, a small RCT of youth with GAD found a tine.44An open-label follow-up study showed that 94% robust response to sertraline after 9 weeks, in contrast to of the fluvoxamine responders exhibited a sustained a low placebo response.45RCTs of medication response benefit after 6 months.44Furthermore, nonresponders to in youth with PTSD indicate limited improvement in RCT Medication Length Dosing Total Ages and Effect size of Number Clinical Notable Author (weeks) (mean) N diagnoses treatment needed outcome/ side effects to treat response rate RUPP Anxiety Fluvoxamine 8 Fixed-flexible. 128 6–17 1.1 2 CGI-I ≤2 Abdominal Study Group, (FLV) (4.0 mg/kg/day) GAD, SoP, SAD FLV 76% discomfort, 200143 PBO 29% ↑Activity Rynn, Siqueland, Sertraline (SER) 9 Fixed. 22 5–17 1.9 1 CGI–I ≤2 & Rickels, 200146 (50 mg) GAD SER 90% PBO 10% Birmaher et al, Fluoxetine (FLX) 12 Fixed. 74 7–17 0.4 4 CGI-I ≤2 Abdominal 200345 (20 mg) GAD, SoP, SAD FLX 61% pain, PBO 35% agitation Wagner et al, Paroxetine (PAR) 16 Flexible. 322 8–17 N/A 3 CGI-I ≤2 Insomnia, 200436 10–50 mg/day SoP PAR 78% ↓Appetite, (24.8 mg) PBO 38% vomiting, agitation Black & Uhde, Fluoxetine (FLX) 12 Fixed. 15 6–11 0.67 N/A CGI-I ≤3 1994133 (0.6 mg/kg/day) Elective mutism FLX 80% PBO 40% Walkup et al, Sertraline (SERT) 12 Fixed-flexible. 488 7-17 COMB=0.86 COMB=1.7 CGI-I ≤2 Insomnia, 200837 COMB (133.7 mg) GAD, SoP, SAD SERT=0.45 SERT=3.2 COMB=80.7%fatigue, SERT (146.0 mg) CBT=0.31 CBT=2.8 SERT=54.9% restlessness CBT=59.7% PBO=23.7 March et al, Venlafaxine ER 16 Weight-based 293 8-17 0.46 5 CGI-I ≤2 Anorexia, 200750 (VFX) flexible. SoP VFX=56% asthenia, (141.5mg) PBO=37% nausea Rynn et al, Venlafaxine ER 8 Weight-based, 320 6-17 0.42 N/A CGI-I ≤2 Headache, 200749 (VFX) flexible. GAD VFX=69% abdominal (pooled studies) PBO=48% pain, anorexia Table I. Randomized controlled trials of SSRIs and SNRIs in pediatric non-OCD anxiety disorders. CGI–I: Clinical Global Impressions-Improvement Scale; COMB: combined; CBT: cognitive-behavioral therapy 442 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 443 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 symptoms with the addition of sertraline to trauma- Safety concerns with SSRIs and SNRIs focused CBT,40 and lack of efficacy compared with placebo after 10 weeks.41Some studies have shown ben- Heightened concern for the negative effects of SSRIs efit from SSRIs,47yet trauma-focused CBT has shown and SNRIs in youth, particularly for activation and more consistent effectiveness.47To date, no RCTs have emerging suicidality, have impacted familial willingness examined medication effects in children or adolescents and clinical practice to initiate treatment with these with panic disorder. agents, particularly for children with anxiety.52Clinical Aside from SSRIs, medications with dual inhibiting practice suggests that children with anxiety tend to be actions on serotonin and norepinephrine (SNRIs) have more sensitive to potential side effects of these medica- also been tested in youth with anxiety disorders. tions, particularly physical discomfort. Lower starting Specifically, venlafaxine XR was examined in two 8- doses should be considered to mitigate these effects. week RCTs in children with GAD. Despite insignificant Other common side effects include nausea, headaches, improvement on a primary measure in one of the trials, sleep abnormalities, and sexual side effects of reduced pooled results revealed significantly greater response in libido and physical responsiveness. Dropouts in RCTs as the active medication group compared with placebo.48 a result of adverse events from SSRIs and SNRIs were Another 16-week RCT of venlafaxine XR in children almost twice as common among subjects taking active with social anxiety showed significant benefit beyond medication compared with placebo.24Side effects tend placebo.49However, studies of venlafaxine in children to emerge earlier in the course of treatment or during indicated a risk for elevated blood pressure, decreased dosage adjustments, and may subside over days to weeks. growth rate, and increased suicidal ideation, which Importantly, antidepressants carry a black-box warning should be considered with families prior to initiating from the FDA out of concern that they may potentiate treatment. A meta-analysis of RCTs examining the tol- suicidal thinking, a low-frequency event that neverthe- erability and efficacy of pharmacotherapy for anxiety less warrants prior consent53and the development of a disorders found that SSRIs and SNRIs showed clear monitoring strategy. Suicidal thoughts may be related to benefit with an overall response rate almost double that the activating effects of SSRIs, resulting in heightened of placebo treatment, with SSRIs slightly more benefi- somatic experiences of anxiety, increased emotional cial than venlafaxine XR.23 lability, and impulsivity. Results from a RCT examining Due to the lack of comparative head-to-head RCTs of activation as a side effect of fluvoxamine in anxious SSRIs or SNRIs, choice of agent is often based on side- youth indicated heightened risk of activation through- effect profiles, interactions with other medications, and out the course of titration.54 family history of medication response. Furthermore, only Despite their relative safety and tolerance, abrupt dis- short-term benefits have been evaluated in RCTs, and continuation of shorter-acting agents often results in research findings may not generalize to clinic popula- generalized discomfort and flu-like symptoms. tions due to exclusion of youth with medical or psychi- Medications often require 4 to 8 weeks to provide clini- atric comorbidities. cal benefit, and potentially longer when starting with low Age may also be an important consideration in phar- doses. Educating families about these expectations and macotherapy. Despite age-related differences in metab- concerns often prevents them from abandoning med- olism and observations that SSRIs may be more effec- ication trials prematurely. tive in the treatment of adolescent depression compared with depressed younger children, findings from RCTs in Tricyclic antidepressants anxious youth do not show differential effects based on age.23,50The evidence base is particularly limited for phar- Tricyclic antidepressants (TCAs) have also shown effi- macologic treatment of anxiety in children under the age cacy in several RCTs of youth with anxiety, particularly of 6.51Given the limited pharmacologic data, CBT, tai- clomipramine, which carries an FDA indication for treat- lored to developmental level, is considered to be the first ment of OCD in children aged 10 and over. RCTs exam- line treatment in children this young. In cases with high ining treatment of social anxiety or school refusal have acuity unresponsive to psychotherapy, medication treat- shown benefits of both imipramine55-57 and ment may be considered. clomipramine.58,59Although TCAs may be considered for 443 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 444 P h a r m a c o l o g i c a l a s p e c t s patients who have experienced intolerance to SSRIs, or promote participation in therapy or school attendance, as augmentation to SSRIs for partial response in youth particularly before SSRIs become effective. No long-term with OCD.60TCAs are generally less preferred because studies are available for use in children, but benzodiaza- they require EKG monitoring due to the potential for pines are noted to have potential for psychological and cardiac abnormalities, carry high risk of fatality in over- physical dependence in adults.64 dose, and have constipation and sedation as side effects. Several other agents have been used in clinical practice, but have more limited support in the literature. Other agents Buspirone, a partial agonist of serotonin receptors, demonstrated effectiveness at 2 weeks with no adverse Controlled trials do not support the use of benzodi- effects compared with placebo in a small placebo-con- azepines in children61,62 yet open-label studies indicate trolled study with mixed anxiety disorders.65 symptomatic benefit,63and multiple agents in this category Central α-agonists, guanfacine and clonidine, have been are used in clinical practice for highly anxious children. considered in treatment of youth with PTSD and dysreg- Prior to initiating treatment, it is important to discuss ulated behavior.66However, controlled research support- management issues, the potential for tolerance, risk of ing the use of these agents is lacking. A small open-label seizure from abrupt discontinuation, and that short-term study of clonidine in patients aged 3 to 6 with PTSD was rather than long-term use is preferred due to addiction shown to decrease arousal, aggression, and anxiety.67 potential. Benzodiazepines can also cause cognitive blunt- Mirtazapine is an antidepressant with some evidence of ing or disinhibition in some children, leading to behavioral efficacy for treating anxiety in adults.68Evidence in youth agitation. Nonetheless, when children have severe symp- is limited, with one positive open-label study for social toms unresponsive to other treatments, benzodiazepine phobia.69This agent may be a consideration to capitalize use early in treatment can help to reduce symptoms and on its sedating and appetite-stimulating properties for Treatment Select SSRI. Titrate up every 2-4 weeks until symptoms respond, → algorithm until side effects preclude further dose increases, → or when reach max dose. If ineffective or intolerable, use alternate SSRI for 2nd trial. → Class SSRI Medication Sertraline Fluoxetine Fluvoxamine Citalopram Paroxetinea Starting dose 12.5-25 mg 5-10 mg 12.5-25 mg 5-10 mg 5–10 mg Total therapeutic 50-200 mg 10-60 mg 50-200 mg 10-40 mg 10-40 mg dose range (Rx bid above 50 mg) Common side-effect Nausea, Activation, Hyperactivity, Somnolence, Sedation, profile sedation, nausea, abdominal discomfort insomnia, nausea, headache insomnia diaphoresis dry mouth Special warning/ Suicidality, activation (restlessness, impulsivity), Serotonin Syndrome; monitoring Develop safety plan and means to assess early side effects, which may resolve in 1-2 weeks; avoid abrupt discontinuation with paroxetine, sertraline, fluvoxamine, and citalopram. Specific indications GAD Long half-life No RCTs; Social phobia; little interactions non-depressed FDA approval For OCD; For OCD; For OCD; For adults For adults ≥ 6 ≥7 ≥8 Table II. Treatment algorithm for pediatric anxiety pharmacotherapy. aIn June 2003, the FDA recommended against the use of paroxetine for Major Depressive Disorder in children and adolescents. EKG, electrocardiogram; BP, blood pressure; 5-HTa PA, serotonin partial agonist; Rx, prescribe; HTN, hypertension; OCD, obsessive-compulsive disorder; SSRI, selective serotonin reuptake inhibitor; GAD, generalized anxiety disorder 444 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 445 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 patients with insomnia or low appetite who are unre- absence of other treatments, it is thought to increase the sponsive to SSRIs. efficacy of psychotherapy by facilitating mechanisms of Propranolol is another agent with some evidence of neuroplasticity.75 effectiveness in adults, but lacks systematic data to sup- Complementary and alternative remedies are often tried port its use in children and adolescents. A crossover pilot by families prior to seeking psychiatric treatment. One study of propranolol in 11 pediatric patients with PTSD study found that “anxiety and stress” was the third most also showed improvements relative to placebo in treat- common reason for the use of complementary and alter- ing symptoms of hyperarousal and intrusivity in the native medicines in children and adolescents.76-77While majority of patients.70 rigorous evidence is lacking to support the use of natur- There are also a variety of other agents that are occa- opathic medications, the plant Kava has some evidence sionally used despite the lack of controlled evidence. For of effectiveness in multiple treatment trials.78In addition, example, buproprion, an inhibitor of dopamine and nor- a review of medicinal plants for the treatment of anxiety epinephrine, has not been studied in children or adoles- disorder found that ginkgo biloba and matricaria recu- cents with anxiety. Similarly, gabapentin has limited evi- tita showed effect sizes similar to those in studies of anti- dence of improvement in anxiety symptoms in adults,71,72 depressants and benzodiazapines.79 but has not been tested in youth. Overall, the use of SSRIs remains the first-line treat- Another intriguing possibility is D-cycloserine, a partial ment, with the best evidence-base. However, for the agonist at the N-methyl-D-aspartate receptor that is patients who can not tolerate or do not benefit from thought to potentiate gains from exposure therapy. Two SSRIs, a variety of other treatment options can be con- RCTs have supported its use as an augmentation strat- sidered. A proposed treatment algorithm is described in egy for youth with OCD73and social anxiety disorder.74 Table II, and is expected to need refinement as clinical While D-cycloserine does not have direct benefits in the evidence grows. After 2 failed SSRI trials, reassess or consult, → If still no response, or familial prefer- → Consider benzodiazepines for acute relief consider clomipramine for OCD; → ence, consider buspirone or mirtazepine, → of severe symptoms or after no response VFX for non-OCD. → alone or as augmentation. → to multiple trials. Tricyclic SNRI 5-HTa PA Tetracyclic Benzodiazepine Clomipramine Venlafaxine XR (VFX) Buspirone Mirtazapine Clonazepam Lorazepam 25 mg 37.5 mg 5 mg tid 7.5-15 mg 0.25-0.5 mg 0.5-1 mg 100–150 mg 75–225 mg 1–60 mg 7.5–30 mg 0.25– mg 0.5– 6 mg (Rx qhs or bid) (Rx tid) (Rx qhs) (Rx qd-tid) (Rx qd-qid) Dry mouth, Nausea, Sedation, Hunger, Sedation, Sedation, constipation, sedation, disinhibition, sedation, confusion confusion diaphoresis dizziness headache dizziness Hypotension, HTN, tachycardia, Safe with Weight gain Disinhibition, Disinhibition, rebound HTN, suicidality benzodiazepines tolerance, tolerance, seizure from lethal in OD; seizure from discontinuation level ≤400 discontinuation OCD; EKG, BP. GAD; Augmentation; Appetite stimulation, Short-term relief Short-term relief of Monitoring to mini- Non-depressed sexual side effects insomnia; of acute anxiety; acute anxiety; shorter mize overdose risk few interactions longer acting acting; liver impaired For OCD; For adults For adults For adults For adults For adults ≥10 Table II. Continued 445 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 446 P h a r m a c o l o g i c a l a s p e c t s Treatment considerations The majority of adolescents with substance abuse disor- informed by diagnosis ders have comorbid psychiatric diagnoses, especially anxiety.83,84 Substance use increases risk for traumatic Youth diagnosed with one anxiety disorder are quite likely events and often interferes with appropriate detection to have multiple anxiety disorders concurrently, including and treatment of anxiety disorders.85 Major Depressive Disorder, Attention Deficit-Hyperactivity Anxiety disorders also pose greater risk for developing Disorder (ADHD), Oppositional Defiant Disorder (ODD) eating disorders, including anorexia nervosa,86and binge and Tourette’s Disorder.36,80In CAMS, among youth who met eating.87Patients may vigilantly attend to food limits to criteria for one or more anxiety disorders, 46% met criteria address their anxiety around eating and its conse- for other internalizing disorders, 11.9% for ADHD, 9.4% for quences, while nutritional benefits often impair brain ODD, and 2.7% for tic disorders.36Providers should there- function and judgment. Fear of eating may further result fore broadly evaluate anxiety symptoms, and assess the in extreme avoidance to psychotherapy. There is mini- degree of impairment thought to be driven by subtypes in mal evidence supporting the use of SSRIs to aid weight order to prioritize treatment. Attention to these comorbidi- restoration,88yet pharmacologic management may nev- ties is essential for comprehensive treatment but may require ertheless be helpful to address co-occurring anxiety or a stepwise approach. depression. Risk factors for having a combination of depression and Children with Autism Spectrum Disorders (ASDs) often anxiety include older age and greater severity of anxiety exhibit agitation and anxious responses to many stimuli, symptoms.80Although most RCTs of anxiety exclude including ritualistic and obsessive behaviors.89The most depressive disorder diagnosis from entry, open-label use common comorbid diagnosis with ASDs is social anxi- of citalopram showed a significantly lower rate of ety disorder.90One meta-analysis of the limited data on response in patients with comorbid anxiety and depres- treatment of children with ASDs found that SSRI treat- sion versus either alone.32 ment was associated with reduced anxiety, decreased Children with behavioral dysregulation as a result of repetitive behaviors, and improved global function.91 anxiety may consequently display features of opposi- However, two recent autism studies using citalopram tionality, leading to diagnoses of disruptive behavior dis- and fluoxetine for ritualistic behaviors were negative, order or ODD. Anxious children may intently refuse to and another meta-analysis raised concerns for lack of comply with demands of authority figures, such as leav- efficacy and risk of side effects when compared with ing the house on time or reading aloud in class, and placebo groups.92,93Clinical recommendations neverthe- refrain from communicating the intense and often less include consideration of SSRI use with symptoms of embarrassing fear that drives this oppositionality. Family anxiety in some children and adolescents with autism psychoeducation and school coordination may thus spectrum disorder.94 reduce conflict. Following treatment, features of exter- Although trichotillomania, or impulsive repetitive hair- nalizing disorders should be re-evaluated. pulling, is listed as an impulse control disorder, the trig- Anxiety disorders in children also often co-occur with gers for repetitive hair-pulling are often anxious ADHD.81Anxious children may have difficulty paying thoughts,95and urges to pull are typically accompanied by attention because of hypervigilance or preoccupation anxiety.95,96However, treatment studies using SSRIs have with peer concerns, as opposed to ADHD-related impair- shown low response rates.97,98CBT with “habit reversal ments. Careful assessment is therefore essential to therapy” is the recommended first-line treatment.99While address the core symptomatology, and also to monitor for co-occurrence of the motor impairments of Tourette’s potential anxiogenic effects of medications during stim- Disorder with OCD is very common, treatment of one ulant trials. Children with ADHD and comorbid anxiety disorder is not thought to significantly impact the symp- who continued to exhibit anxious features following stim- tomatic impairments related to the other.100 ulant treatment did not exhibit any further anxiety ben- In contrast to pharmacotherapy for anxiety disorders in efit from the addition of fluvoxamine to their stimulant youth, there are many more FDA approved-medications regimen when compared with adding a placebo,82indi- for the treatment of anxiety in adults. These include mul- cating that polypharmacy should not be assumed to con- tiple benzodiazepindes (alprazolam, clomipramine, clo- fer improved efficacy in comorbid disorders. razepate, lorazepam, oxazepam); multiple SSRIs (parox- 446 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 447 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 etine, fluoxetine, fluvoxamine, escitalopram, sertraline); repeated confinement results in behavioral changes sug- SNRIs (venlafaxine); tricyclics (amitriptyline), MAO gestive of anxiety and depression. Neuroatanomic inhibitors (phenelzine), and miscellaneous agents (bus- changes include significant decreases in prefrontal and pirone and hydroxyzine). These findings do not neces- hippocampal neuron dendrites, including reduced length, sarily support use in youth. branching, and postsynaptic spine number.107This mor- phologic plasticity may initially be an adaptive response Neuroscience perspectives on anxiety to potential cytotoxicity, limiting vulnerability from disorders and treatments exposed excitatory receptors,108 but when excessive, eventually leads to impairments in structural plastic- As described elsewhere in this issue, anxiety disorders in ity.109,110 Despite the known adverse effects of severe children and adults involve alterations in fear respon- stress on neuronal circuitry and plasticity,111some stress- sivity, driven by adjustments in the tuning of specific ful experiences may actually confer future resilience, components of fear circuitry.101,102 Excessive fear particularly under later high stress conditions.112,113 responses are further thought to induce lasting structural Similar to synaptogenesis and dendritic remodeling, neu- changes in several components of synaptic connectivity rogenesis is understood as a lifelong adaptive brain and plasticity, contributing to the maintenance of anxi- response which may be impacted by anxiety and its treat- ety symptomatology, even when stressors are strictly ments. Neurogenesis is upregulated by experiential fac- avoided.103 Increasing understanding of anxiety treat- tors such as enriched experience, while decreased in ments, including both pharmacotherapy and CBT, many animal paradigms of stress and depression.114 reveals that beyond avoiding stressors or simply forget- Similarly, the expression of neurotrophins and their ting past associations, alleviating the negative impact of receptors, thought to underlie rapid changes in dendritic experiences requires active learning mechanisms, and synaptic architecture, is impaired by stress and thought to reorganize brain structure and function. enhanced under many learning conditions.115Interference Behavioral improvements in animal models of anxiety with neurogenesis or neurotrophic factor production in are thus prevented when these plasticity mechanisms are the hippocampus prevents the behavioral effects of anti- experimentally inhibited.104Successful treatments likely depressants to improve fearful responses in experimen- facilitate further neuronal adaptation to meet the tal animals.116Medications and CBT may therefore ame- demands of appropriately responding to stressful stim- liorate maladaptive structural and neurochemical uli. Improvements in the understanding of neural cir- responses by increasing the resilience of stress circuitry cuitry related to this adaptive resilience, in addition to to impairments in neuronal and synaptic proliferation, understanding the processes that catalyze change in thus allowing greater synaptic connectivity, adaptability, these circuits, allows for emerging neuronal targets to and preserved function.107 enhance treatment. This notion is supported by experimental findings of Multiple types of learning are known to induce struc- SSRI-induced trophic changes in several neuronal ele- tural adaptation in brain connectivity and function, and ments, including promoting neurotrophin expression and this response is tailored to meet the demands of the spe- neurogenesis in brain regions relevant to anxiety disor- cific learning tasks; while the aerobic demands of tread- ders.117SSRIs have been shown to block the impairing mill activity induce greater blood vessel growth in rat effect of stress on hippocampal neurogenesis and induce cerebellar cortex, the increased learning demands of both improved behavioral responses and elevations in acrobat training are associated with growth of synaptic multiple synaptic remodeling proteins.118Furthermore, connectivity, termed synaptogenesis.105Stress can induce chronic, but not acute, administration of SSRIs increase emotional learning and similarly cause a specific pat- the expression of neurotrophic factors,115suggesting that terns of alterations in synaptic architecture. Evidence the delay in clinical response to SSRIs may reflect the from human childhood trauma studies suggest these time course of neurogenesis or other changes in neu- alterations may become maladaptive in extreme stress, ronal excitability.11 resulting in future volumetric reductions in hippocam- Several other antianxiety medications, including SNRIs, pal regions when associated with subsequent PTSD.106 have been found to normalize behavior, and also restore Rodent models of chronic restraint stress (CRS) from neurotrophin levels, in experimental animals. After 447 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 448 P h a r m a c o l o g i c a l a s p e c t s repeated restraint stress to rats, venlafaxine accelerated but should focus on facilitating more adaptive neuronal restoration of neurotrophin levels and hippocampal neu- reorganization by enhancing the mechanisms of plastic- rogenesis.120Duloxetine was also shown to increase local ity thought to be impaired as a consequence of patho- neurotrophin transcription at synapses, enhancing plas- logic anxiety.115Multiple forms of treatment may work ticity, and this effect was only seen after chronic admin- synergistically to enhance this adaptive response. Future istration.121 pharmacologic agents might allow for greater precision Several of the mediators known to affect anxiety respon- in targeting specific neuronal elements thought to mod- sivity, including both stressful experiences and thera- ulate this process, particularly those affected in various peutic medications, are further thought to operate forms of psychiatric illness. through epigenetic mechanisms involving changes in the regulation of chromatin arrangements by histone pro- Conclusion teins.122,123Similar neurotrophic effects in animals, medi- ated by histone acetylation, are seen following environ- Anxiety disorders are common in children and adoles- mental enrichment treatments, with improved plasticity cents, and contribute to significant impairments in qual- and learning, even in mice with history of severe stress ity of life, often stemming from behavioral avoidance that or neurodegeneration.124-126 may limit normative developmental tasks. While there As neurogenesis is limited to circumscribed brain regions are many more RCTs of pharmacologic treatment of after early brain development, and SSRIs have been anxiety disorders in adults as compared with youth, there shown to induce synaptic remodeling and behavioral is increasing evidence that carefully implemented inter- improvements even when neurogenesis is prevented,127it vention with medications improves symptoms in children is unlikely that one plasticity mechanism is solely respon- and adolescents, particularly when high acuity is present. sible for the improvements related to pharmacotherapy Best practice is for a combination approach of CBT for anxiety and mood disorders. Indeed, aside from which adheres to manualized models, coupled with med- changes in synaptic architecture, neurochemical, physio- ications. SSRIs are the agents of first choice for anxiety logic, hormonal, and molecular mediators are also disorders, with subsequent switch to an alternative SSRI thought to play essential roles in the response to stress if a first trial is not successful. Other medication options, and its treatments.128Furthermore, while neuronal plas- including use of tricyclic antidepressants and short-term ticity and dendritic enhancements allow for change and use of benzodiazepines, may be considered, but lack the implementation of more adaptive neuronal networks, evidence base and carry additional risks. they may also confer risk to greater consolidation of mal- Emerging evidence from animal and human studies sug- adaptive responses,129as proliferation is not strictly adap- gests that anxiety disorders are associated with changes tive. In fact, dendritic proliferation is selectively increased in neuronal structure and function, and that effective in some amygdala and orbitofrontal neurons in response treatments with psychotherapy or medications refine to stress, and is thought to contribute to impaired reac- these abnormalities in a number of ways. Future treat- tivity.130,131 ments may focus on enhancing this process to allow These findings broadly indicate that anxiety treatments emotional learning to facilitate resilience, as opposed to should not exclusively target neurotransmitter deficits contributing to maladaptive stress reactivity. ❏ REFERENCES 4. Irwin C. The adolescent visit. In: Rudolph C, Rudolph A, Hostetter M, Lister G, Siegel N, eds. Rudolph's Pediatrics.21st ed. New York, NY: McGraw 1. Pine DS, Guyer AE, Leibenluft E. Functional magnetic resonance imaging Hill; 2002:234-238. and pediatric anxiety. J Am Acad Child Adolesc Psychiatry. 2008;47:1217-1221. 5. Rockhill CM, Kodish I, DiBattisto C, et al. Anxiety disorders in chil- 2. Krystal JH, Tolin DF, Sanacora G, et al. Neuroplasticity as a target for the dren and adolescents. Curr Probl Pediatr Adolesc Health Care. 2010;40:67- pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. 99. Drug Discov Today. 2009;14:690-697. 6. Jellinek M, Murphy J, Robinson J, et al. Pediatric symptom checklist 3. Centers for Disease Control and Prevention, NCHS Health eStat. U.S. (PSC): screening school-age children for psychosocial dysfunction. J Pediatr. children 4-17 years of age who received treatment for emotional or behav- 1988;112:201-209. ioral difficulties: Preliminary data from the. 2005 National Health Interview 7. Chiang O. Anxiety disorders. In: Garfunkel L, Kaczorowski J, Christy C, Survey. Available at: http://www.cdc.gov/nchs/data/hestat/children2005/chil- eds. Mosby's Pediatric Clinical Advisor: Instant Diagnosis and Treatment. 2nd ed. dren2005.htm. Accessed August 28, 2010. St. Louis, MO: Mosby, Inc; 2007. 448

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PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 439 P h a r m a c o l o g i c a l a s p e c t s Pharmacotherapy for anxiety disorders in children and adolescents Ian Kodish, MD, PhD; Carol Rockhill, MD, PhD; Chris Varley, MD Introduction A nxiety is a normal response to environmental stressors, and promotes safety by facilitating behavioral avoidance of threatening stimuli. This sense of threat is modulated by fear circuitry, including amygdala, hip- pocampus, and prefrontal regions. Anxiety disorders are thought to involve alterations in fear responsivity, driven Anxiety disorders are the most common mental health by adjustments in the tuning of specific circuit compo- diagnoses in youth, and carry risks for ongoing impair- nents, including deficiencies in the dampening of amyg- ments and subsequent development of other psychiatric dala stress responses by prefrontal regions.1The neuronal comorbidities into adulthood. This article discusses con- circuitry involved in the regulation of anxiety operates siderations for assessment and treatment of anxiety dis- within a context of environmental cues and across a orders in youth, with a focus on the evidence base of developmental landscape, such that assessment of nor- pharmacologic treatment and important clinical consid- mal developmental tasks and environmental stressors are erations to optimize care. We then briefly describe the essential for clinical evaluation. The distress associated impact of anxiety on neuronal elements of fear circuitry with clinical anxiety often elicits intense escape urges, to highlight how treatments may ameliorate impairments offering immediate symptom relief. This avoidance is so through enhanced plasticity. Overall, pharmacotherapy reinforcing that it may rapidly become habitual, resulting for anxiety disorders is effective in improving clinical symp- in increasingly impaired functioning. Treatment requires toms, particularly in combination with psychotherapy. reducing reinforcements associated with avoidance while Response is typically seen within several weeks, yet longi- gradually empowering youth to tolerate anxiety in the tudinal studies are limited. Selective serotonin reuptake face of potentially stressful challenges. inhibitors are thought to be relatively safe and effective Pharmacologic interventions may confer clinical benefit for acute treatment of several classes of anxiety disorders by reducing the degree of anxious reactivity, thereby in youth, with increasing evidence supporting the role of Author affiliations: Acting Assistant Professor, Department of Psychiatry neuronal plasticity in recovery. and Behavioral Sciences, University of Washington School of Medicine, © 2011, LLS SAS Dialogues Clin Neurosci.2011;13:439-452. Seattle, WA (Ian Kodish, Carol Rockhill); Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Keywords:anxiety disorder; pharmacotherapy; selective serotonin reuptake inhi- Medicine, Seattle, WA (Chris Varley) bitor; child; plasticity Address for correspondence:Ian Kodish, MD,PhD, Seattle Children’s Hospital, 4800 Sandpoint Way NE, Seattle, WA 98105 USA (e-mail: [email protected]) Copyright © 2011 LLS SAS. All rights reserved 439 www.dialogues-cns.org PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 440 P h a r m a c o l o g i c a l a s p e c t s increasing the range of opportunities for children to optimum management of symptoms, yet excessive test- learn more adaptive responses to stressful stimuli. With ing or otherwise providing reinforcement of symptom successful treatment, extinction of recurrent anxiety emergence through heightened interventions is not rec- symptoms is thought to require neuronal plasticity to ommended. take effect, similar to other forms of learning. Selective serotonin uptake inhibitors (SSRIs) and other treatment Treatment of anxiety disorders modalities are thought to facilitate these neurochemical and neuroanatomical enhancements, contributing to A multimodal treatment approach, including a combi- clinical effectiveness.2This enhanced neuroplasticity may nation of medication, therapy, and environmental inter- also contribute to better response rates by augmenting ventions, is increasingly shown to confer greater other interventions such as psychotherapy. improvement in symptoms compared with unimodal treatments. Although the essential elements of success- Assessment and diagnosis of anxiety ful therapy are not clear, cognitive-behavioral therapy (CBT) studies have extensively demonstrated effective- Initial identification of anxiety disorders in children and ness in individual, group, and family formats.9 adolescents often occurs during medical visits to primary Randomized controlled trials (RCTs) of CBT have care providers. Presenting concerns typically include shown benefit for Generalized Anxiety Disorder avoidance of age-appropriate tasks, or excessive physical (GAD),10-14social anxiety disorder,10-14panic disorder,13 complaints such as headaches, dizziness, or stomachaches, obsessive–compulsive disorder (OCD),14-16and post-trau- which are particularly common presenting signs of anxi- matic stress disorder (PTSD).18These benefits have also ety at younger ages.3Physical complaints related to anx- been found to be maintained over time.19Therefore, for iety can be diverse,4and are often highly concerning to youth who meet criteria for anxiety disorders with mild- parents. A timeline of physical, psychological, and behav- to-moderate functional impairments, the American ioral symptoms, elicited from both the child and parents, Academy of Child and Adolescent Psychiatry recom- is valuable to assess the evolution of symptoms and con- mends psychoeducation for patients and their families sider exacerbating factors. A broad review focused on the and initially deferring use of medication to CBT.20 association between symptoms and psychosocial stress is However, for youth with moderate to severe anxiety also recommended, including past medical history and symptoms, multimodal treatment is recommended, family history of psychiatric illnesses and substance including medication in combination with CBT.21 abuse. General screening measures tailored to develop- Multiple RCTs support the efficacy of SSRIs, both alone mental level are available for providers to help identify and in combination with therapy, for the treatment of children with psychosocial difficulties,5and self-reports anxiety disorders in children and adolescents. may help to identify anxiety in children who are disin- Medication intervention may be started concurrently clined to reveal symptoms during examination.6 with psychotherapy, or may be initiated before starting therapy to reduce the impairing nature of severe symp- Medical evaluation toms and promote treatment effectiveness. Medication can also be added after engagement in CBT if initial psy- Despite the potential for physical symptoms to represent chotherapy does not provide satisfactory relief of symp- somatic complaints driven by anxiety, consideration of toms. It is important to recognize that both psychother- common medical issues related to anxiety disorders is apy and medication management result in improvement, essential.9,7Physical examination and judicious labora- but not necessarily in full remission of symptoms. tory testing targeting potential underlying relevant med- When considering pharmacologic agents, selection ical problems should be performed.8Common screens should be guided by the evidence base and clinical include tests for endocrine abnormalities (thyroid and guidelines, with special consideration for side-effect pro- fasting glucose), urine toxicology, respiratory problems, files and unique clinical characteristics to optimally tai- sleep abnormalities, cardiac conduction defects (partic- lor care. Informed consent is required from parents, and ularly if considering tricyclic agents), and seizure activ- when possible, from the child or adolescent. States vary ity. Pertinent findings can guide more specialized and in policies regarding obtaining consent or assent from 440 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 441 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 youth. Even if not required, direct discussion of med- The highest regarded clinical trial examining the impact ication use with the patient is likely to improve compli- of both manualized psychotherapy and medication on ance and engagement irrespective of age. symptoms of OCD in youth is the Pediatric OCD When initiating medications, frequent visits with the pre- Treatment Study (POTS). In this study, sertraline’s effec- scriber, typically every 2 to 4 weeks, are recommended tiveness in pediatric OCD for 12 weeks was compared to closely monitor for effectiveness and tolerance. with CBT, combined treatment, and placebo.13 Each Regular communication between the prescriber and the active treatment arm proved superior to placebo, and treating therapist is also encouraged. More frequent combined treatment was superior to either CBT or ser- provider contact is also recommended when there is a traline alone. Another RCT examining sertraline for history of depression, a strong familial preference, or youth with OCD also found significantly greater when compliance is a concern. Standardized rating scales improvement after active treatment compared with should be used to measure treatment effectiveness. After placebo,24 with lasting effects in 70% of patients who an effective dose of medication is reached, visit fre- were examined 12 months later.35 quency may be reduced. Even after symptom resolution, A 10-week RCT of pediatric outpatients with OCD cautious treatment calls for medication maintenance for showed fluvoxamine to be effective.27Despite the com- 1 year, followed by a gradual tapering off to allow obser- mon clinical finding that weeks of treatment with SSRIs vation of any recurrence of symptoms.22 are required prior to symptom response, improvements beyond placebo were evident by the first week and Evidence for effectiveness of showed gains through the course of treatment. SSRIs and SNRIs Other SSRIs with RCTs demonstrating effectiveness in the treatment of pediatric OCD include paroxetine28,29 A limited number of RCTs have evaluated antianxiety and fluoxetine.25,26Notably, fluoxetine treatment required agents in children and adolescents. To date, no medica- 8 weeks prior to showing effectiveness over placebo, and tions have been approved by the FDA for treatment of a higher dose only lengthened this response time. non-OCD anxiety in youth. Four medications have been Secondary analyses also showed that paroxetine demon- approved for OCD treatment in children and adoles- strated significantly lower response rates among youth cents. Medication and placebo response rates range with OCD and comorbid illness such as ADHD, tic dis- across studies, which are difficult to compare due to lim- orders, or oppositional defiant disorder (ODD).29 ited clinical samples and variability in measures of Overall, these clinical studies suggest a moderate treat- assessment and clinical response. Yet positive results ment effect that is relatively similar across SSRIs.23 have been demonstrated for multiple agents in the treat- Despite the much greater prevalence of non-OCD anx- ment of anxiety in both youth and adults, particularly iety disorders, studies are more limited in children and medications targeting serotonin reuptake. A meta-analy- adolescents. Furthermore, subtypes are often mixed sis of RCTs examining the tolerability and efficacy of within treatment arms, limiting the ability to compare pharmacotherapy for anxiety disorders in youth found response to treatment by specific disorder. Nevertheless, that SSRIs and SNRIs showed clear benefit with an RCTs of SSRIs have demonstrated efficacy in the treat- overall response rate almost double that of placebo.23 ment of GAD, separation anxiety disorder (SAD), and Regarding specific pediatric anxiety subtypes, OCD has social phobia, often in mixed populations with any one the largest number of positive RCTs, which reveal clin- or a combination of these (Table I). Although the data ical benefit after treatment with sertraline,15,24 fluoxe- are limited, the average likelihood of pharmacologic tine,25,26 fluvoxamine,27 or paroxetine.28,29 Evidence for treatment response for non-OCD disorders appears to citalopram is limited to open-label studies30-32and com- be slightly greater than for OCD.23 parison with fluoxetine without placebo.33 SSRIs are The largest RCT of non-OCD anxiety disorders to date first-line therapy for pharmacologic management of anx- is the Childhood Anxiety Multimodal Study (CAMS), iety disorders in youth, and three of the four medications which evaluated treatment of SAD, GAD, and social approved by the FDA for treatment of OCD in children phobia.36Treatment groups included sertraline only, CBT and adolescents are SSRIs: sertraline (≥6), fluoxetine only,37 combination treatment, or placebo. All three (≥7), and fluvoxamine (≥8).3 active treatments were superior to placebo (24%), with 441 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 442 P h a r m a c o l o g i c a l a s p e c t s the highest response in the combined condition. These initial fluvoxamine treatment still exhibited a high rate findings again suggest that, while monotherapy with of response to a subsequent open-label trial of fluoxe- either medication or psychotherapy alone can be effec- tine, supporting the clinical benefit of a subsequent trial tive for treating anxiety disorders, a multimodal using alternative SSRIs despite an initial lack of approach is more likely to be successful. This method is response to one agent. also thought to apply to pediatric depression38and com- Fewer studies have examined selective cohorts with plex forms of ADHD,39while evidence for combination diagnoses of specific non-OCD anxiety disorders. An therapy is limited for youth with PTSD.40,41 RCT examining paroxetine treatment in youth specifi- Other agents with demonstrated efficacy for youth with cally with social anxiety showed efficacy over placebo.35 non-OCD anxiety include fluvoxamine42,43and fluoxe- In addition, a small RCT of youth with GAD found a tine.44An open-label follow-up study showed that 94% robust response to sertraline after 9 weeks, in contrast to of the fluvoxamine responders exhibited a sustained a low placebo response.45RCTs of medication response benefit after 6 months.44Furthermore, nonresponders to in youth with PTSD indicate limited improvement in RCT Medication Length Dosing Total Ages and Effect size of Number Clinical Notable Author (weeks) (mean) N diagnoses treatment needed outcome/ side effects to treat response rate RUPP Anxiety Fluvoxamine 8 Fixed-flexible. 128 6–17 1.1 2 CGI-I ≤2 Abdominal Study Group, (FLV) (4.0 mg/kg/day) GAD, SoP, SAD FLV 76% discomfort, 200143 PBO 29% ↑Activity Rynn, Siqueland, Sertraline (SER) 9 Fixed. 22 5–17 1.9 1 CGI–I ≤2 & Rickels, 200146 (50 mg) GAD SER 90% PBO 10% Birmaher et al, Fluoxetine (FLX) 12 Fixed. 74 7–17 0.4 4 CGI-I ≤2 Abdominal 200345 (20 mg) GAD, SoP, SAD FLX 61% pain, PBO 35% agitation Wagner et al, Paroxetine (PAR) 16 Flexible. 322 8–17 N/A 3 CGI-I ≤2 Insomnia, 200436 10–50 mg/day SoP PAR 78% ↓Appetite, (24.8 mg) PBO 38% vomiting, agitation Black & Uhde, Fluoxetine (FLX) 12 Fixed. 15 6–11 0.67 N/A CGI-I ≤3 1994133 (0.6 mg/kg/day) Elective mutism FLX 80% PBO 40% Walkup et al, Sertraline (SERT) 12 Fixed-flexible. 488 7-17 COMB=0.86 COMB=1.7 CGI-I ≤2 Insomnia, 200837 COMB (133.7 mg) GAD, SoP, SAD SERT=0.45 SERT=3.2 COMB=80.7%fatigue, SERT (146.0 mg) CBT=0.31 CBT=2.8 SERT=54.9% restlessness CBT=59.7% PBO=23.7 March et al, Venlafaxine ER 16 Weight-based 293 8-17 0.46 5 CGI-I ≤2 Anorexia, 200750 (VFX) flexible. SoP VFX=56% asthenia, (141.5mg) PBO=37% nausea Rynn et al, Venlafaxine ER 8 Weight-based, 320 6-17 0.42 N/A CGI-I ≤2 Headache, 200749 (VFX) flexible. GAD VFX=69% abdominal (pooled studies) PBO=48% pain, anorexia Table I. Randomized controlled trials of SSRIs and SNRIs in pediatric non-OCD anxiety disorders. CGI–I: Clinical Global Impressions-Improvement Scale; COMB: combined; CBT: cognitive-behavioral therapy 442 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 443 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 symptoms with the addition of sertraline to trauma- Safety concerns with SSRIs and SNRIs focused CBT,40 and lack of efficacy compared with placebo after 10 weeks.41Some studies have shown ben- Heightened concern for the negative effects of SSRIs efit from SSRIs,47yet trauma-focused CBT has shown and SNRIs in youth, particularly for activation and more consistent effectiveness.47To date, no RCTs have emerging suicidality, have impacted familial willingness examined medication effects in children or adolescents and clinical practice to initiate treatment with these with panic disorder. agents, particularly for children with anxiety.52Clinical Aside from SSRIs, medications with dual inhibiting practice suggests that children with anxiety tend to be actions on serotonin and norepinephrine (SNRIs) have more sensitive to potential side effects of these medica- also been tested in youth with anxiety disorders. tions, particularly physical discomfort. Lower starting Specifically, venlafaxine XR was examined in two 8- doses should be considered to mitigate these effects. week RCTs in children with GAD. Despite insignificant Other common side effects include nausea, headaches, improvement on a primary measure in one of the trials, sleep abnormalities, and sexual side effects of reduced pooled results revealed significantly greater response in libido and physical responsiveness. Dropouts in RCTs as the active medication group compared with placebo.48 a result of adverse events from SSRIs and SNRIs were Another 16-week RCT of venlafaxine XR in children almost twice as common among subjects taking active with social anxiety showed significant benefit beyond medication compared with placebo.24Side effects tend placebo.49However, studies of venlafaxine in children to emerge earlier in the course of treatment or during indicated a risk for elevated blood pressure, decreased dosage adjustments, and may subside over days to weeks. growth rate, and increased suicidal ideation, which Importantly, antidepressants carry a black-box warning should be considered with families prior to initiating from the FDA out of concern that they may potentiate treatment. A meta-analysis of RCTs examining the tol- suicidal thinking, a low-frequency event that neverthe- erability and efficacy of pharmacotherapy for anxiety less warrants prior consent53and the development of a disorders found that SSRIs and SNRIs showed clear monitoring strategy. Suicidal thoughts may be related to benefit with an overall response rate almost double that the activating effects of SSRIs, resulting in heightened of placebo treatment, with SSRIs slightly more benefi- somatic experiences of anxiety, increased emotional cial than venlafaxine XR.23 lability, and impulsivity. Results from a RCT examining Due to the lack of comparative head-to-head RCTs of activation as a side effect of fluvoxamine in anxious SSRIs or SNRIs, choice of agent is often based on side- youth indicated heightened risk of activation through- effect profiles, interactions with other medications, and out the course of titration.54 family history of medication response. Furthermore, only Despite their relative safety and tolerance, abrupt dis- short-term benefits have been evaluated in RCTs, and continuation of shorter-acting agents often results in research findings may not generalize to clinic popula- generalized discomfort and flu-like symptoms. tions due to exclusion of youth with medical or psychi- Medications often require 4 to 8 weeks to provide clini- atric comorbidities. cal benefit, and potentially longer when starting with low Age may also be an important consideration in phar- doses. Educating families about these expectations and macotherapy. Despite age-related differences in metab- concerns often prevents them from abandoning med- olism and observations that SSRIs may be more effec- ication trials prematurely. tive in the treatment of adolescent depression compared with depressed younger children, findings from RCTs in Tricyclic antidepressants anxious youth do not show differential effects based on age.23,50The evidence base is particularly limited for phar- Tricyclic antidepressants (TCAs) have also shown effi- macologic treatment of anxiety in children under the age cacy in several RCTs of youth with anxiety, particularly of 6.51Given the limited pharmacologic data, CBT, tai- clomipramine, which carries an FDA indication for treat- lored to developmental level, is considered to be the first ment of OCD in children aged 10 and over. RCTs exam- line treatment in children this young. In cases with high ining treatment of social anxiety or school refusal have acuity unresponsive to psychotherapy, medication treat- shown benefits of both imipramine55-57 and ment may be considered. clomipramine.58,59Although TCAs may be considered for 443 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 444 P h a r m a c o l o g i c a l a s p e c t s patients who have experienced intolerance to SSRIs, or promote participation in therapy or school attendance, as augmentation to SSRIs for partial response in youth particularly before SSRIs become effective. No long-term with OCD.60TCAs are generally less preferred because studies are available for use in children, but benzodiaza- they require EKG monitoring due to the potential for pines are noted to have potential for psychological and cardiac abnormalities, carry high risk of fatality in over- physical dependence in adults.64 dose, and have constipation and sedation as side effects. Several other agents have been used in clinical practice, but have more limited support in the literature. Other agents Buspirone, a partial agonist of serotonin receptors, demonstrated effectiveness at 2 weeks with no adverse Controlled trials do not support the use of benzodi- effects compared with placebo in a small placebo-con- azepines in children61,62 yet open-label studies indicate trolled study with mixed anxiety disorders.65 symptomatic benefit,63and multiple agents in this category Central α-agonists, guanfacine and clonidine, have been are used in clinical practice for highly anxious children. considered in treatment of youth with PTSD and dysreg- Prior to initiating treatment, it is important to discuss ulated behavior.66However, controlled research support- management issues, the potential for tolerance, risk of ing the use of these agents is lacking. A small open-label seizure from abrupt discontinuation, and that short-term study of clonidine in patients aged 3 to 6 with PTSD was rather than long-term use is preferred due to addiction shown to decrease arousal, aggression, and anxiety.67 potential. Benzodiazepines can also cause cognitive blunt- Mirtazapine is an antidepressant with some evidence of ing or disinhibition in some children, leading to behavioral efficacy for treating anxiety in adults.68Evidence in youth agitation. Nonetheless, when children have severe symp- is limited, with one positive open-label study for social toms unresponsive to other treatments, benzodiazepine phobia.69This agent may be a consideration to capitalize use early in treatment can help to reduce symptoms and on its sedating and appetite-stimulating properties for Treatment Select SSRI. Titrate up every 2-4 weeks until symptoms respond, → algorithm until side effects preclude further dose increases, → or when reach max dose. If ineffective or intolerable, use alternate SSRI for 2nd trial. → Class SSRI Medication Sertraline Fluoxetine Fluvoxamine Citalopram Paroxetinea Starting dose 12.5-25 mg 5-10 mg 12.5-25 mg 5-10 mg 5–10 mg Total therapeutic 50-200 mg 10-60 mg 50-200 mg 10-40 mg 10-40 mg dose range (Rx bid above 50 mg) Common side-effect Nausea, Activation, Hyperactivity, Somnolence, Sedation, profile sedation, nausea, abdominal discomfort insomnia, nausea, headache insomnia diaphoresis dry mouth Special warning/ Suicidality, activation (restlessness, impulsivity), Serotonin Syndrome; monitoring Develop safety plan and means to assess early side effects, which may resolve in 1-2 weeks; avoid abrupt discontinuation with paroxetine, sertraline, fluvoxamine, and citalopram. Specific indications GAD Long half-life No RCTs; Social phobia; little interactions non-depressed FDA approval For OCD; For OCD; For OCD; For adults For adults ≥ 6 ≥7 ≥8 Table II. Treatment algorithm for pediatric anxiety pharmacotherapy. aIn June 2003, the FDA recommended against the use of paroxetine for Major Depressive Disorder in children and adolescents. EKG, electrocardiogram; BP, blood pressure; 5-HTa PA, serotonin partial agonist; Rx, prescribe; HTN, hypertension; OCD, obsessive-compulsive disorder; SSRI, selective serotonin reuptake inhibitor; GAD, generalized anxiety disorder 444 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 445 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 patients with insomnia or low appetite who are unre- absence of other treatments, it is thought to increase the sponsive to SSRIs. efficacy of psychotherapy by facilitating mechanisms of Propranolol is another agent with some evidence of neuroplasticity.75 effectiveness in adults, but lacks systematic data to sup- Complementary and alternative remedies are often tried port its use in children and adolescents. A crossover pilot by families prior to seeking psychiatric treatment. One study of propranolol in 11 pediatric patients with PTSD study found that “anxiety and stress” was the third most also showed improvements relative to placebo in treat- common reason for the use of complementary and alter- ing symptoms of hyperarousal and intrusivity in the native medicines in children and adolescents.76-77While majority of patients.70 rigorous evidence is lacking to support the use of natur- There are also a variety of other agents that are occa- opathic medications, the plant Kava has some evidence sionally used despite the lack of controlled evidence. For of effectiveness in multiple treatment trials.78In addition, example, buproprion, an inhibitor of dopamine and nor- a review of medicinal plants for the treatment of anxiety epinephrine, has not been studied in children or adoles- disorder found that ginkgo biloba and matricaria recu- cents with anxiety. Similarly, gabapentin has limited evi- tita showed effect sizes similar to those in studies of anti- dence of improvement in anxiety symptoms in adults,71,72 depressants and benzodiazapines.79 but has not been tested in youth. Overall, the use of SSRIs remains the first-line treat- Another intriguing possibility is D-cycloserine, a partial ment, with the best evidence-base. However, for the agonist at the N-methyl-D-aspartate receptor that is patients who can not tolerate or do not benefit from thought to potentiate gains from exposure therapy. Two SSRIs, a variety of other treatment options can be con- RCTs have supported its use as an augmentation strat- sidered. A proposed treatment algorithm is described in egy for youth with OCD73and social anxiety disorder.74 Table II, and is expected to need refinement as clinical While D-cycloserine does not have direct benefits in the evidence grows. After 2 failed SSRI trials, reassess or consult, → If still no response, or familial prefer- → Consider benzodiazepines for acute relief consider clomipramine for OCD; → ence, consider buspirone or mirtazepine, → of severe symptoms or after no response VFX for non-OCD. → alone or as augmentation. → to multiple trials. Tricyclic SNRI 5-HTa PA Tetracyclic Benzodiazepine Clomipramine Venlafaxine XR (VFX) Buspirone Mirtazapine Clonazepam Lorazepam 25 mg 37.5 mg 5 mg tid 7.5-15 mg 0.25-0.5 mg 0.5-1 mg 100–150 mg 75–225 mg 1–60 mg 7.5–30 mg 0.25– mg 0.5– 6 mg (Rx qhs or bid) (Rx tid) (Rx qhs) (Rx qd-tid) (Rx qd-qid) Dry mouth, Nausea, Sedation, Hunger, Sedation, Sedation, constipation, sedation, disinhibition, sedation, confusion confusion diaphoresis dizziness headache dizziness Hypotension, HTN, tachycardia, Safe with Weight gain Disinhibition, Disinhibition, rebound HTN, suicidality benzodiazepines tolerance, tolerance, seizure from lethal in OD; seizure from discontinuation level ≤400 discontinuation OCD; EKG, BP. GAD; Augmentation; Appetite stimulation, Short-term relief Short-term relief of Monitoring to mini- Non-depressed sexual side effects insomnia; of acute anxiety; acute anxiety; shorter mize overdose risk few interactions longer acting acting; liver impaired For OCD; For adults For adults For adults For adults For adults ≥10 Table II. Continued 445 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 446 P h a r m a c o l o g i c a l a s p e c t s Treatment considerations The majority of adolescents with substance abuse disor- informed by diagnosis ders have comorbid psychiatric diagnoses, especially anxiety.83,84 Substance use increases risk for traumatic Youth diagnosed with one anxiety disorder are quite likely events and often interferes with appropriate detection to have multiple anxiety disorders concurrently, including and treatment of anxiety disorders.85 Major Depressive Disorder, Attention Deficit-Hyperactivity Anxiety disorders also pose greater risk for developing Disorder (ADHD), Oppositional Defiant Disorder (ODD) eating disorders, including anorexia nervosa,86and binge and Tourette’s Disorder.36,80In CAMS, among youth who met eating.87Patients may vigilantly attend to food limits to criteria for one or more anxiety disorders, 46% met criteria address their anxiety around eating and its conse- for other internalizing disorders, 11.9% for ADHD, 9.4% for quences, while nutritional benefits often impair brain ODD, and 2.7% for tic disorders.36Providers should there- function and judgment. Fear of eating may further result fore broadly evaluate anxiety symptoms, and assess the in extreme avoidance to psychotherapy. There is mini- degree of impairment thought to be driven by subtypes in mal evidence supporting the use of SSRIs to aid weight order to prioritize treatment. Attention to these comorbidi- restoration,88yet pharmacologic management may nev- ties is essential for comprehensive treatment but may require ertheless be helpful to address co-occurring anxiety or a stepwise approach. depression. Risk factors for having a combination of depression and Children with Autism Spectrum Disorders (ASDs) often anxiety include older age and greater severity of anxiety exhibit agitation and anxious responses to many stimuli, symptoms.80Although most RCTs of anxiety exclude including ritualistic and obsessive behaviors.89The most depressive disorder diagnosis from entry, open-label use common comorbid diagnosis with ASDs is social anxi- of citalopram showed a significantly lower rate of ety disorder.90One meta-analysis of the limited data on response in patients with comorbid anxiety and depres- treatment of children with ASDs found that SSRI treat- sion versus either alone.32 ment was associated with reduced anxiety, decreased Children with behavioral dysregulation as a result of repetitive behaviors, and improved global function.91 anxiety may consequently display features of opposi- However, two recent autism studies using citalopram tionality, leading to diagnoses of disruptive behavior dis- and fluoxetine for ritualistic behaviors were negative, order or ODD. Anxious children may intently refuse to and another meta-analysis raised concerns for lack of comply with demands of authority figures, such as leav- efficacy and risk of side effects when compared with ing the house on time or reading aloud in class, and placebo groups.92,93Clinical recommendations neverthe- refrain from communicating the intense and often less include consideration of SSRI use with symptoms of embarrassing fear that drives this oppositionality. Family anxiety in some children and adolescents with autism psychoeducation and school coordination may thus spectrum disorder.94 reduce conflict. Following treatment, features of exter- Although trichotillomania, or impulsive repetitive hair- nalizing disorders should be re-evaluated. pulling, is listed as an impulse control disorder, the trig- Anxiety disorders in children also often co-occur with gers for repetitive hair-pulling are often anxious ADHD.81Anxious children may have difficulty paying thoughts,95and urges to pull are typically accompanied by attention because of hypervigilance or preoccupation anxiety.95,96However, treatment studies using SSRIs have with peer concerns, as opposed to ADHD-related impair- shown low response rates.97,98CBT with “habit reversal ments. Careful assessment is therefore essential to therapy” is the recommended first-line treatment.99While address the core symptomatology, and also to monitor for co-occurrence of the motor impairments of Tourette’s potential anxiogenic effects of medications during stim- Disorder with OCD is very common, treatment of one ulant trials. Children with ADHD and comorbid anxiety disorder is not thought to significantly impact the symp- who continued to exhibit anxious features following stim- tomatic impairments related to the other.100 ulant treatment did not exhibit any further anxiety ben- In contrast to pharmacotherapy for anxiety disorders in efit from the addition of fluvoxamine to their stimulant youth, there are many more FDA approved-medications regimen when compared with adding a placebo,82indi- for the treatment of anxiety in adults. These include mul- cating that polypharmacy should not be assumed to con- tiple benzodiazepindes (alprazolam, clomipramine, clo- fer improved efficacy in comorbid disorders. razepate, lorazepam, oxazepam); multiple SSRIs (parox- 446 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 447 Pharmacotherapy for childhood anxiety disorders - Kodish et al Dialogues in Clinical Neuroscience - Vol 13 .No. 4 .2011 etine, fluoxetine, fluvoxamine, escitalopram, sertraline); repeated confinement results in behavioral changes sug- SNRIs (venlafaxine); tricyclics (amitriptyline), MAO gestive of anxiety and depression. Neuroatanomic inhibitors (phenelzine), and miscellaneous agents (bus- changes include significant decreases in prefrontal and pirone and hydroxyzine). These findings do not neces- hippocampal neuron dendrites, including reduced length, sarily support use in youth. branching, and postsynaptic spine number.107This mor- phologic plasticity may initially be an adaptive response Neuroscience perspectives on anxiety to potential cytotoxicity, limiting vulnerability from disorders and treatments exposed excitatory receptors,108 but when excessive, eventually leads to impairments in structural plastic- As described elsewhere in this issue, anxiety disorders in ity.109,110 Despite the known adverse effects of severe children and adults involve alterations in fear respon- stress on neuronal circuitry and plasticity,111some stress- sivity, driven by adjustments in the tuning of specific ful experiences may actually confer future resilience, components of fear circuitry.101,102 Excessive fear particularly under later high stress conditions.112,113 responses are further thought to induce lasting structural Similar to synaptogenesis and dendritic remodeling, neu- changes in several components of synaptic connectivity rogenesis is understood as a lifelong adaptive brain and plasticity, contributing to the maintenance of anxi- response which may be impacted by anxiety and its treat- ety symptomatology, even when stressors are strictly ments. Neurogenesis is upregulated by experiential fac- avoided.103 Increasing understanding of anxiety treat- tors such as enriched experience, while decreased in ments, including both pharmacotherapy and CBT, many animal paradigms of stress and depression.114 reveals that beyond avoiding stressors or simply forget- Similarly, the expression of neurotrophins and their ting past associations, alleviating the negative impact of receptors, thought to underlie rapid changes in dendritic experiences requires active learning mechanisms, and synaptic architecture, is impaired by stress and thought to reorganize brain structure and function. enhanced under many learning conditions.115Interference Behavioral improvements in animal models of anxiety with neurogenesis or neurotrophic factor production in are thus prevented when these plasticity mechanisms are the hippocampus prevents the behavioral effects of anti- experimentally inhibited.104Successful treatments likely depressants to improve fearful responses in experimen- facilitate further neuronal adaptation to meet the tal animals.116Medications and CBT may therefore ame- demands of appropriately responding to stressful stim- liorate maladaptive structural and neurochemical uli. Improvements in the understanding of neural cir- responses by increasing the resilience of stress circuitry cuitry related to this adaptive resilience, in addition to to impairments in neuronal and synaptic proliferation, understanding the processes that catalyze change in thus allowing greater synaptic connectivity, adaptability, these circuits, allows for emerging neuronal targets to and preserved function.107 enhance treatment. This notion is supported by experimental findings of Multiple types of learning are known to induce struc- SSRI-induced trophic changes in several neuronal ele- tural adaptation in brain connectivity and function, and ments, including promoting neurotrophin expression and this response is tailored to meet the demands of the spe- neurogenesis in brain regions relevant to anxiety disor- cific learning tasks; while the aerobic demands of tread- ders.117SSRIs have been shown to block the impairing mill activity induce greater blood vessel growth in rat effect of stress on hippocampal neurogenesis and induce cerebellar cortex, the increased learning demands of both improved behavioral responses and elevations in acrobat training are associated with growth of synaptic multiple synaptic remodeling proteins.118Furthermore, connectivity, termed synaptogenesis.105Stress can induce chronic, but not acute, administration of SSRIs increase emotional learning and similarly cause a specific pat- the expression of neurotrophic factors,115suggesting that terns of alterations in synaptic architecture. Evidence the delay in clinical response to SSRIs may reflect the from human childhood trauma studies suggest these time course of neurogenesis or other changes in neu- alterations may become maladaptive in extreme stress, ronal excitability.11 resulting in future volumetric reductions in hippocam- Several other antianxiety medications, including SNRIs, pal regions when associated with subsequent PTSD.106 have been found to normalize behavior, and also restore Rodent models of chronic restraint stress (CRS) from neurotrophin levels, in experimental animals. After 447 PAGES_12_AG_1005_BA.qxd:DCNS#51 1/12/11 14:54 Page 448 P h a r m a c o l o g i c a l a s p e c t s repeated restraint stress to rats, venlafaxine accelerated but should focus on facilitating more adaptive neuronal restoration of neurotrophin levels and hippocampal neu- reorganization by enhancing the mechanisms of plastic- rogenesis.120Duloxetine was also shown to increase local ity thought to be impaired as a consequence of patho- neurotrophin transcription at synapses, enhancing plas- logic anxiety.115Multiple forms of treatment may work ticity, and this effect was only seen after chronic admin- synergistically to enhance this adaptive response. Future istration.121 pharmacologic agents might allow for greater precision Several of the mediators known to affect anxiety respon- in targeting specific neuronal elements thought to mod- sivity, including both stressful experiences and thera- ulate this process, particularly those affected in various peutic medications, are further thought to operate forms of psychiatric illness. through epigenetic mechanisms involving changes in the regulation of chromatin arrangements by histone pro- Conclusion teins.122,123Similar neurotrophic effects in animals, medi- ated by histone acetylation, are seen following environ- Anxiety disorders are common in children and adoles- mental enrichment treatments, with improved plasticity cents, and contribute to significant impairments in qual- and learning, even in mice with history of severe stress ity of life, often stemming from behavioral avoidance that or neurodegeneration.124-126 may limit normative developmental tasks. While there As neurogenesis is limited to circumscribed brain regions are many more RCTs of pharmacologic treatment of after early brain development, and SSRIs have been anxiety disorders in adults as compared with youth, there shown to induce synaptic remodeling and behavioral is increasing evidence that carefully implemented inter- improvements even when neurogenesis is prevented,127it vention with medications improves symptoms in children is unlikely that one plasticity mechanism is solely respon- and adolescents, particularly when high acuity is present. sible for the improvements related to pharmacotherapy Best practice is for a combination approach of CBT for anxiety and mood disorders. Indeed, aside from which adheres to manualized models, coupled with med- changes in synaptic architecture, neurochemical, physio- ications. SSRIs are the agents of first choice for anxiety logic, hormonal, and molecular mediators are also disorders, with subsequent switch to an alternative SSRI thought to play essential roles in the response to stress if a first trial is not successful. Other medication options, and its treatments.128Furthermore, while neuronal plas- including use of tricyclic antidepressants and short-term ticity and dendritic enhancements allow for change and use of benzodiazepines, may be considered, but lack the implementation of more adaptive neuronal networks, evidence base and carry additional risks. they may also confer risk to greater consolidation of mal- Emerging evidence from animal and human studies sug- adaptive responses,129as proliferation is not strictly adap- gests that anxiety disorders are associated with changes tive. In fact, dendritic proliferation is selectively increased in neuronal structure and function, and that effective in some amygdala and orbitofrontal neurons in response treatments with psychotherapy or medications refine to stress, and is thought to contribute to impaired reac- these abnormalities in a number of ways. Future treat- tivity.130,131 ments may focus on enhancing this process to allow These findings broadly indicate that anxiety treatments emotional learning to facilitate resilience, as opposed to should not exclusively target neurotransmitter deficits contributing to maladaptive stress reactivity. ❏ REFERENCES 4. Irwin C. The adolescent visit. In: Rudolph C, Rudolph A, Hostetter M, Lister G, Siegel N, eds. Rudolph's Pediatrics.21st ed. New York, NY: McGraw 1. Pine DS, Guyer AE, Leibenluft E. Functional magnetic resonance imaging Hill; 2002:234-238. and pediatric anxiety. J Am Acad Child Adolesc Psychiatry. 2008;47:1217-1221. 5. Rockhill CM, Kodish I, DiBattisto C, et al. Anxiety disorders in chil- 2. Krystal JH, Tolin DF, Sanacora G, et al. Neuroplasticity as a target for the dren and adolescents. Curr Probl Pediatr Adolesc Health Care. 2010;40:67- pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia. 99. Drug Discov Today. 2009;14:690-697. 6. Jellinek M, Murphy J, Robinson J, et al. Pediatric symptom checklist 3. Centers for Disease Control and Prevention, NCHS Health eStat. U.S. (PSC): screening school-age children for psychosocial dysfunction. J Pediatr. children 4-17 years of age who received treatment for emotional or behav- 1988;112:201-209. ioral difficulties: Preliminary data from the. 2005 National Health Interview 7. Chiang O. Anxiety disorders. In: Garfunkel L, Kaczorowski J, Christy C, Survey. Available at: http://www.cdc.gov/nchs/data/hestat/children2005/chil- eds. Mosby's Pediatric Clinical Advisor: Instant Diagnosis and Treatment. 2nd ed. dren2005.htm. Accessed August 28, 2010. St. Louis, MO: Mosby, Inc; 2007. 448

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