Ann. N.Y. Acad. Sci. ISSN 0077-8923
A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Childhood Onset Developmental Disorders
Treatment of pediatric anxiety disorders Amy Rapp,1 Alice Dodds,2 John T. Walkup,3 and Moira Rynn1 1 3
New York State Psychiatric Institute, New York, New York. 2 Drexel University College of Medicine, Philadelphia, Pennsylvania. Weill Cornell Medical College and NewYork–Presbyterian Hospital, New York, New York
Address for correspondence: Moira Rynn, New York State Psychiatric Institute, 1051 Riverside Drive, Box 74, New York, NY 10032. [email protected]
This article provides a brief review of the current available data concerning present treatment and potential new treatment advances for pediatric anxiety disorders, such as generalized anxiety disorder, separation anxiety disorder, social phobia, obsessive–compulsive disorder, and posttraumatic stress disorder. Disorder-specific treatment methods and innovations, particularly computer-assisted methods of delivery for cognitive behavioral therapy (CBT) will be reviewed. Additionally, the paper will discuss novel psychopharmacological compounds (e.g., d-cycloserine, riluzole, memantine, and anticonvulsant medications). Available evidence for the efficacy of novel medication strategies in adult studies and implications for their use in pediatrics will be discussed. Keywords: cognitive behavioral therapy; pharmacotherapy; pediatric; anxiety
Introduction This article will briefly review both cognitive behavioral therapy (CBT) and psychopharmacological treatments for youth anxiety disorders, with a focus on emerging treatment approaches. Thus, for CBT we will highlight interventions that utilize a group format and/or new methods of treatment dissemination, as well as considerations for partial or nonresponders to first-line treatments. Currently, cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment for pediatric anxiety disorders. Yet it is estimated that about 20–35% of patients who receive these treatments show little benefit.1,2 Therefore, research continues to be focused on developing additional treatments to either replace or augment our current treatment paradigms. Many of the novel medication treatments target the N-methyl-d-aspartate (NMDA) system, which has been implicated in emotional learning and fear extinction.3 In this article, we will explore some of the current literature on new potential compounds for the treatment of pediatric anxiety disorders; these include d-cylcoserine, N-acetylcysteine, memantine, riluzole, anticonvulsant medications, and propranolol.
Please note that the anxiety studies reviewed in this article used the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria.4 Childhood anxiety disorders appear in DSM V within the chapters that discuss similar disorders found in adults. However, obsessive–compulsive disorder (OCD) is now listed in the category “OCD and Related Disorders” and posttraumatic stress disorder (PTSD) is now under the category “Trauma- and Stressor-Related Disorders” with developmentally sensitive criteria thresholds.5 Generalized anxiety disorder, social phobia, and separation anxiety disorder
Combination treatment (CBT plus SSRI) The Child/Adolescent Anxiety Multimodal Study (CAMS) remains the largest pediatric anxiety randomized clinical trial (RCT).2 This study compared the efficacy of Coping Cat (the manual-based CBT intervention) alone, sertraline alone, pill placebo, and the combination CBT and sertraline treatment, in 488 children and adolescents with a primary diagnosis of separation anxiety disorder (SAD), social phobia (SoP), and/or generalized anxiety disorder (GAD). All treatments were significantly superior to placebo. However, combination treatment led to significantly higher response rates compared to CBT doi: 10.1111/nyas.12318
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alone, sertraline alone, or pill placebo (81% versus 60% versus 55% versus 24%, respectively). Response rates for CBT alone and sertraline alone were not significantly different. Restlessness, fatigue, sedation, and insomnia were reported more often by participants receiving sertraline than those receiving CBT. No suicidal attempts were reported. Five participants (3.6%) receiving CBT alone and five participants receiving combination treatment (3.6%) reported suicidal ideation (P = ns). Ginsburg et al.6 found similar results when examining remission rates in the CAMS study; all treatments remained superior to placebo, with the combination treatment leading to significantly higher remission rates than sertraline alone, CBT alone, or pill placebo (46– 68% versus 34–46% versus 20–46% versus 15–27%, respectively). Both sertraline alone and CBT alone led to significantly higher remission rates than pill placebo, but rates were not different from each other. Factors associated with remission were absence of comorbid internalizing disorders, absence of SoP, lower baseline anxiety severity, nonminority status, and younger age. In fact, participants with SoP at baseline were significantly less likely to achieve remission across treatment conditions compared to those without SoP. Additionally, the majority of participants had some residual anxiety symptoms after 12 weeks of treatment. However, this large anxiety trial confirms that the field has three efficacious treatment approaches: CBT, SSRI, and the combination of these two treatments. There is a need to do further research related to additional comorbid diagnoses and outcome. Presently, there is an ongoing follow up study to the CAMs sample that should provide helpful information on long-term outcomes. Given that CBT is a well-established and efficacious treatment for this anxiety triad in youth, there remains the challenge of access to this specialized treatment.2,6,7 A new area of treatment that is emerging is computer-based and computer-assisted CBT interventions, which increase accessibility, allow for additional privacy, and are cost effective.8 Below we have highlighted two computer-based and computer-assisted interventions for the anxiety triad. Camp Cope-A-Lot (CCAL). CCAL is a 12-session intervention for youth aged 7–13 years that have an anxiety disorder(s) that can be implemented
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by providers without previous CBT training. The computer-assisted program includes a therapist, or coach, in addition to computerized sessions. CCAL was compared to individual CBT (ICBT) and a computer-linked education, support, and attention (CESA) condition in one RCT (N = 49) by Khanna and Kendall.9 At posttreatment, 70% of participants randomized to ICBT and 81% of participants randomized to CCAL no longer carried principal diagnoses, compared to 19% of those assigned to CESA. Independent evaluator–rated severity and functioning also indicated gains over time. Ratings of satisfaction, therapist adherence, flexibility, and alliance were also obtained. Therapist adherence was significantly greater for CCAL (t (40) = 2.1, P < 0.05) and CESA (t (33) = 3.2, P < 0.01) compared to ICBT. Therapeutic alliance was consistently rated across conditions; however, ratings of therapist flexibility were greater for ICBT (F2,39 = 10.9, P < 0.01) than for CCAL (t (38) = 3.5, P < 0.01) and CESA (t (33) = 2.6, P < 0.05). Parent ratings of treatment satisfaction did not differ significantly across treatment assignments; however, child-reported satisfaction was significantly higher for both CCAL and ICBT when compared to CESA (F2,45 = 6.1, P < 0.05; F2, 45 = 3.36, P < 0.05, respectively). Results from this study indicate that children assigned to receive CCAL showed similarly significant improvement in anxiety severity and global functioning compared to ICBT. Of note, ratings of CCAL therapist adherence were greater than those for ICBT. Such findings suggest that CCAL may be a promising intervention and may reduce therapist deviation from treatment manuals commonly seen in community practice. BRAVE-ONLINE. The BRAVE-ONLINE program is an adaptation of a clinic-based CBT intervention for anxiety-disordered youth aged 7–14 years. The acronym BRAVE stands for five anxietymanagement strategies: body signs (detecting physiological symptoms of anxiety), relax (mindfulness, deep breathing, guided imagery), activate helpful thoughts (cognitive restructuring and coping self-talk), victory over fears (exposure components and problem solving), and enjoy yourself (self-reward).10 This intervention is delivered over 10 weekly sessions plus two additional sessions for skill consolidation and relapse prevention. In addition to the computerized software, the intervention also includes weekly online contact and two phone
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contacts with a therapist.11 March et al.12 compared BRAVE-ONLINE (henceforth referred to as internet-based CBT (NET)) to a waitlist condition. At posttreatment, nine of 30 youth (30%) assigned to receive NET no longer met criteria for a primary anxiety disorder compared to three of 29 (10.3%) youth in the waitlist condition, as determined by combined parent and child reports on the parent version of the Anxiety Disorders Interview Schedule (ADIS-P) and the child version of the ADIS (ADIS-C). Improved clinical outcomes in previous trials of clinic-based CBT have been reported; however, outcomes at a 6-month follow-up were consistent with previous studies (i.e., 75% of children no longer had their primary anxiety diagnosis). The authors acknowledge adherence as a limitation of postintervention gains, with only 60% of parents and 33.3% of children completing all therapy sessions at 10 weeks. In a recent RCT,13 NET was compared to an active control (clinic-based CBT) and a waitlist condition. At posttreatment, both NET and clinic-based CBT produced clinically significant improvement, as defined by CSR less than or equal to three for the primary anxiety diagnosis. Fifteen of 41 participants (36.6%) in the completer sample in the NET condition and 13 of 40 participants (32.5%) in the clinic-based CBT arm demonstrated significant improvement at posttreatment. In the waitlist condition, one of 24 participants (4.2%) demonstrated significant improvement at posttreatment. These results suggest that online CBT may have treatment potential and is worth continued study. The differences in the response rates between BRAVE and CCAL may reflect differences in the adherence and makeup of the anxiety diagnoses, with BRAVE having a higher percentage of youth suffering from SoP. Evidence suggests that the treatment response to CBT is not necessarily consistent across anxiety disorders. Youth with a principal diagnosis of SoP were shown to demonstrate a less favorable treatment outcome compared to youth with a principal diagnosis of GAD or SAD.14 Kendall et al. drew attention to common characteristics of youth with SoP who participated in the Crawley et al. study that could explain this discrepancy, including: high occurrence of comorbidity, greater degree of impairment at baseline, and older age. Other factors, such as parent psychopathology, depression comorbidity, and self-consciousness, may also contribute to limited improvement posttreatment.14 Additionally, Beidel 54
et al. showed that both fluoxetine and Social Effectiveness Therapy for Children (SET-C) are efficacious treatments for reducing social distress in adolescents with social phobia. However, SET-C appears to provide additional benefits compared to fluoxetine alone by improving social skills.15 Moreover, adding social skills training for youth with social phobia may augment treatment response.6 Behavioral activation, such as social skills training and peer exposure integrated into treatment, may facilitate the child’s use of anxiety-management skills.14 The identification of these distinctions between youth with SoP compared to those with GAD or SAD indicates the need to better understand change processes during treatment for these youth. Such insight may contribute to treatment personalization and the development of targeted augmentation strategies for partial or nonresponders.8
Experimental pharmacological approaches Presently, the first-line medication treatment of pediatric triad anxiety disorders is the SSRI class of medication. There are numerous controlled trials that support this class of medication for its efficacy and safety. Additionally, there are studies examining the potential efficacy of benzodiazepines, serotonin– norepinephrine reuptake inhibitors, and buspirone (see review by Rynn et al.16 ). With reference to new medication approaches for children and adolescents who do not respond to first-line treatment, there are few studies in the pediatric population evaluating other medication treatment options and most are in the adult population, as reviewed in this article. Anticonvulsant medications Currently, no studies have examined the use of anticonvulsants to treat pediatric anxiety disorders. It is hypothesized that anticonvulsants may treat anxiety disorders through their actions on ␥ -aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the brain.17 In an RCT of levetiracetam for the treatment of adult social anxiety disorder, Stein et al.18 did not find a significant difference in response rates between levetiracetam and placebo (41.3% versus 46.6%, respectively; P > 0.05). In contrast, RCTs of pregabalin have shown promising results in adults for the treatment of GAD,19,20 and SoP.20 Pregabalin has also been shown to decrease relapse rates in adults with SoP.21 Furthermore, research has suggested that pregabalin may reduce anxiety and withdrawal symptoms
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in adults with GAD on long-term benzodiazepine therapy.22 Across these studies, medication treatment was well-tolerated, with the major side effects including somnolence and dizziness. However, other studies on patients with epilepsy have highlighted several psychopathological side effects associated with anticonvulsant treatment, including affective disorders, aggression, and psychosis.17,23 Research by Mula et al. found that patients with a personal or family history of psychiatric disease were more likely to develop these side effects.17 Clearly, research on the use of anticonvulsants in children with anxiety disorders is needed to further elucidate their safety and efficacy even for consideration as an alternative for treatment of refractory cases. Obsessive–compulsive disorder
CBT CBT is considered a first-line treatment for OCD in youth. Exposure and response prevention (E/RP), a type of CBT that gradually implements exposure to feared stimuli under patient or therapist control, is often administered in this population.24 However, investigation of adjunctive interventions for youth with OCD receiving CBT is warranted, particularly for youth who display unwillingness to engage in treatment. One randomized trial (N = 16) assigned participants to receive CBT plus motivational interviewing (MI) or CBT plus psychoeducation (control) for up to 14 sessions over 3 weeks.25 For those randomized to receive CBT plus MI, three MI sessions took place at specific time points in the treatment during which hesitation or fears might be expected to peak (i.e., pretreatment, after completing exposure homework independently, and when participants reach the highest level of fear hierarchies). Outcome was measured by the Children’s Yale– Brown Obsessive–Compulsive Scale (CYBOCS) total score and CGI severity/improvement. Although at posttreatment, there were no significant differences in outcome measures between the two groups, significant reductions in CYBOCS scores were noted following the second MI session (mean change = 16.75, SD = 9.66) and third MI session (mean change = 21.38, SD = 9.12) compared to the same time points for youth in the control condition (mean change = 8.31, SD = 6.01; mean change = 13.13, SD = 9.01, respectively). These preliminary results suggest that incorporating MI sessions may accelerate treatment gains, thus shortening the duration of
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treatment, and have practical implications for families by minimizing the travel time and financial cost associated with treatment. As noted previously in this article, although CBT is efficacious for treating youth anxiety disorders, adherence to CBT may be challenging for some youth. Web-based adaptations may be helpful in overcoming this limitation. Computer and webbased interventions have been developed for adults with OCD, but few options exist for youth with OCD. One RCT (n = 31)26 randomized participants to receive a web-based adaptation (W-CBT) of the treatment protocol used in the Pediatric OCD Treatment Study (POTS)1 or a waitlist condition. At posttreatment, average CYBOCS reduction was greater for the W-CBT arm than the waitlist condition (56.1% versus 12.9%). Criteria for remission was met by nine of 16 participants (56%) assigned to WCBT compared to two of 15 participants (13%) assigned to the control. However, this study’s promising preliminary findings are limited by its lack of an active-control comparator arm (i.e., clinic-based CBT). Future trials of W-CBT are warranted to provide further insight into overcoming implementation challenges of this intervention, such as difficulties in establishing a therapeutic alliance. One clinical trial targeted medication partial responders or nonresponders to at least two or more trials of SSRIs and/or SSRI augmented by an atypical antipsychotic.27 Study participants (n = 30) received 14 sessions of intensive family-based CBT over 3 weeks. Parental involvement was required at all sessions. Significant differences in CYBOCS severity were demonstrated from pre- to posttreatment (t (29) = 10.60, P < 0.001) and maintained at follow-up (t (29) = –0.13, P > 0.05). Additionally, at posttreatment, 17 of 30 participants (56.6%) were considered to have reached remission status as defined by a severity rating on the ADIS-IV-P of less than or equal to 3 and a CYBOCS total score less than or equal to 10. At the 3-month follow-up, 16 of 30 participants (53.3%) maintained remission status. These results corroborate the use of CBT as a first-line treatment for OCD and suggest that intensive family-based CBT may be particularly relevant for treatment-resistant youth.
Combination treatment The Pediatric OCD Treatment Study examined the efficacy of sertraline alone, CBT alone, and the
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combination of CBT and medication compared to placebo. Similar to the findings in CAMS, combination treatment significantly decreased symptoms of OCD on the primary outcome measure (combined, P = 0.001; sertraline, P = 0.007; and CBT, P = 0.003). When the sample was examined for those youth achieving excellent response, the combination treatment and CBT alone were not significantly different, and medication treatment did not differ significantly from placebo. This suggests that when a child is able to engage in CBT treatment, it is reasonable to treat first with CBT alone, with the option to add an SSRI if CBT is not effective.
Experiment pharmacological treatments D-Cycloserine. Research in both animals and adults has suggested that d-cycloserine may augment the effects of CBT treatment in children and adolescents with anxiety disorders.28–33 Storch et al.34 conducted a preliminary RCT on d-cycloserine augmentation of CBT in pediatric OCD. Thirty participants were randomized to receive either d-cycloserine or placebo 1 h before CBT treatment. No significant difference was found between treatment groups. However, CBT plus dcylcoserine showed small to moderate treatment effects on primary outcome measures (d = 0.31– 0.47). Riluzole. Current research on the pathophysiology of OCD has suggested that excess glutamate, the primary excitatory neurotransmitter in the brain, may underlie OCD. Riluzole is a potent glutaminergic antagonist and therefore offers a novel therapy for targeting the overactive glutamate pathway. Open-label trials and case studies in adults with anxiety disorders have demonstrated that Riluzole is an effective treatment for OCD,35 GAD,36 trichotillomania,37 eating disorder, and skin-picking behavior.38 One open-label trial of Riluzole in six pediatric patients with treatmentresistant OCD found that four participants responded during the 12 week trial, and one participant responded after trial completion.39 Although no participants discontinued the study, two participants had elevated liver transaminases. An RCT of Riluzole in pediatric OCD has been recently completed at the National Institute of Mental Health (NIMH);40 this study includes participants with comorbid autism spectrum disorders. Preliminary tolerability results from 46 participants in56
clude two participants who developed pancreatitis while on concomitant medications and one participant with baseline steatosis who developed elevated transaminases. All three participants recovered completely once Riluzole was discontinued. Memantine. This is a noncompetitive antagonist of the NMDA receptor that is thought to protect neurons from the neurotoxic effects of glutamate.41 One single-blind study42 on memantine for the treatment of OCD in adults showed promising results. However, case studies on memantine as an augmenting agent in treating adult OCD have had mixed results.43–45 Currently, no clinical trials have examined the use of memantine in pediatric anxiety disorders. However, Hezel et al.46 described a case report of a 15-year-old female patient with OCD refractory to treatment who had a robust response to memantine, with only mild to subclinical symptoms after 1 month of treatment. She did not show any signs of relapse at her 9-month follow-up. All studies reported good tolerance to memantine. Posttraumatic stress disorder
CBT Trauma-focused CBT (TF-CBT). Evidence is most robust for trauma-focused CBT (TF-CBT) among CBT approaches for treating symptoms of PTSD in youth.47 TF-CBT is often provided to youth who have experienced past trauma; it is appropriate for youth aged 3–18 years and is generally delivered over 12–20 sessions.48 The intervention consists of nine components referred to by the acronym PRACTICE: psychoeducation, parenting skills, relaxation skills, affective modulation skills, cognitive coping skills, trauma narration and processing, in vivo mastery of trauma reminders, conjoint child– parent sessions, and enhancing safety.48 Formal exposure is a critical component of TF-CBT; however, Cohen et al.49 raised the appropriateness of exposure work for youth experiencing ongoing trauma. The authors suggest that additional considerations may need to be taken, including enhancing safety early in treatment, increasing parental engagement, and optimally focusing the trauma narration and processing, when treating this population of youth with TF-CBT. Nixon et al.50 compared TF-CBT to trauma-focused cognitive therapy (TF-CT) in a recent RCT (n = 34). The lack of an exposure component distinguishes TF-CT from TF-CBT. At
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posttreatment, both arms demonstrated reduced symptom severity, with 65% of participants in the TF-CBT arm and 56% of participants in the TF-CT arm meeting remission criteria. These results suggest that nonexposure based treatment may be a viable option for treating youth experiencing ongoing trauma. Two recently published RCTs examined effectiveness of TF-CBT. Sixty-four youth were enrolled in an RCT51 to assess the effectiveness of TF-CBT in very young children aged 3–6 years. A second RCT (N = 124) aimed to evaluate TF-CBT compared to child-centered therapy (CCT) for children with PTSD symptoms following experiences of intimate partner violence (IPV).52 In both studies, reduction in PTSD symptoms was greater in the TF-CBT arm than in the comparator arm. One follow-up study53 investigated the maintenance of TF-CBT treatment gains at 6 and 12 months posttreatment; the treatment gains were sustained at both assessment points. Finally, Dorsey et al. reviewed several CBT approaches that have a strong evidence base or are “promising practices” for the treatment of PTSD in youth.47 Three group interventions are highlighted in the following section. Cognitive–Behavioral Intervention for Trauma in Schools (CBITS). CBITS is a 10-session intervention that includes individual sessions and teacher education, as well as optional parent sessions. This school-based treatment was initially designed for youth exposed to violence in the community. However, CBITS has been adapted for youth with a range of trauma experiences (e.g., recent immigration54 ) and also for implementation in nonschool settings. Stein et al.55 conducted an RCT (N = 126) comparing CBITS to a waitlist-delayed intervention group. After 3 months, the comparator group also received CBITS. Assessments of symptoms and functioning were administered at baseline, 3 months, and 6 months. Self-reported symptoms of PTSD, as assessed using the Child PTSD Symptom Scale, were significantly lower for participants assigned to early intervention compared to the delayed intervention group at the 3-month posttreatment follow-up (8.9 versus 15.5). However, significant differences were not preserved at a 6-month follow-up after both groups received the intervention. Parent reports of psychosocial dysfunction, as assessed by the Pediatric Symptom Checklist, were also significantly re-
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duced for youth assigned to early intervention (12.5 versus 16.5). Similarly to child reports of symptoms at 6 months, parent reports of psychosocial dysfunction were not significantly different between early intervention and delayed intervention groups (9.4 versus 8.9). Teacher reports of classroom behavior, as assessed by the Teacher–Child Rating Scale, revealed no significant differences between early intervention and delayed intervention groups at both 3 and 6 months. CBITS is a promising treatment model for implementation in school and community settings. Structured Psychotherapy for Adolescents Responding to Chronic Stress (SPARCS). SPARCS is a present-focused, developmentally sensitive intervention delivered over 16 sessions for youth aged 12–21 years.56 It implements common elements of CBT (excluding an exposure component) and Dialectic Behavioral Therapy to address the needs of youth with complex trauma histories and who have been exposed to chronic interpersonal trauma. Weiner et al.57 aimed to study the cross-cultural effectiveness of three treatments: SPARCS, Child– Parent Psychotherapy, and TF-CBT. In this pilot study (N = 133), 33 youth aged 13–21 years were enrolled to receive SPARCS. The intervention improved functioning in multiple domains across ethnic subgroups and reduced problems as rated by the Child and Adolescent Needs and Strengths tool in African-American youth. Combined Parent–Child Cognitive-Behavioral Approach for Children and Families At-Risk for Child Physical Abuse (CPC-CBT). CPC-CBT differs from existing interventions for families at risk for physical child abuse since it includes pediatric PTSD symptoms as a primary treatment focus. The treatment utilizes a 16-week multifamily group design of 2-h sessions involving concurrent parent and child interventions, followed by parent–child joint sessions. One RCT (N = 75) compared CPC-CBT to parent-only CBT.58 Children included in treatment (i.e., assigned to the CPC-CBT arm) experienced greater improvement in PTSD symptoms compared to children who were not included in treatment. Furthermore, parents assigned to the CPC-CBT arm reported greater improvements in positive parenting, as assessed by the Alabama Parenting Questionnaire, compared to parent-only treatment.
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Combination treatment Cohen et al.59 compared TF-CBT plus sertraline to TF-CBT plus pill placebo in a pilot study for the treatment of PTSD in sexually abused children. The sample consisted of 24 female participants aged 10–17 years and diagnosed with PTSD (92%) or posttraumatic stress syndrome. Both groups experienced a significant reduction in PTSD symptoms, without any significant difference in response across treatments. Experimental pharmacological treatments Propranolol has been studied as a potential treatment for PTSD. By blocking the adrenergic system, propanolol may inhibit memory consolidation.60 Only two studies have explored the use of propranolol in pediatric anxiety, and neither found significant results. Nugent et al.61 conducted an RCT on the use of propranolol in pediatric injury victims. Twenty-nine participants started on propranolol or placebo within 12 h of a traumatic event, and then assessed for PTSD symptoms 6 weeks later. At follow-up, only one participant (4%) met criteria for PTSD, and 11 (42%) met criteria for partial PTSD. No significant difference was found between treatment groups for diagnostic status, PTSD symptoms, or heart rate during trauma narrative. However, there was a significant trend for elevated PTSD symptoms in adherent girls in the propranolol group compared to the placebo group (R2 = 0.44, P = 0.05). Also, there was a nonsignificant trend for decreased PTSD symptoms in adherent boys in the propranolol group compared to the placebo group (R2 = 0.32, P = 0.09). Although history of a prior trauma did not predict current PTSD symptomatology, it is intriguing that participants in the propranolol group who had fewer PTSD symptoms were often male without a history of prior trauma, and those who had more PTSD symptoms were often female with a history of trauma. These findings highlight that gender and prior trauma history may influence patient response to early propranolol intervention. One retrospective review by Sharp et al.62 found no difference in the prevalence of acute stress disorder among pediatric burn victims treated with propranolol compared to those who didn’t receive propranolol (8% versus 5%, respectively). One pilot RCT (N = 41) has been done on the use of propranolol (40 mg, four times daily) for 58
the treatment of adult PTSD.63 Treatment began within 6 h of the traumatic event. At 1 month, mean PTSD score, as measured by the ClinicianAdministered PTSD Scale (CAPS), did not differ between treatment groups. Rates of PTSD at 1 month were lower in the propranolol group compared to placebo but failed to reach statistical significance (18% versus 30%, P = 0.39). These nonsignificant results may be secondary to an outlier in the propranolol group that had a mean CAPS score that was five standard deviations greater than the mean for that group. At the 3-month follow-up, the propranolol-treated group showed decreased physiological responses to traumatic imagery compared to the placebo group (0% versus 43%, P = 0.04), but failed to show a significant difference in PTSD rates (11% versus 13%, P = 0.62). An open-label trial64 and one case report65 support the use of propranolol in preventing as well as treating adult PTSD. One RCT (N = 19)66 and three open-label trials60 on the administration of propranolol during trauma reactivation sessions have also shown positive results in adults. Despite these positive findings, using propranolol to prevent and treat adult PTSD remains controversial because of the medication’s effects on personal memory.67 Prazosin is effective for combat-related PTSD with trauma nightmares in active-duty soldiers.68 Raskind et al. showed that Prazosin was effective for all three primary outcome measures: combat-related trauma nightmares, sleep quality, and global status. However, substantial residual symptoms suggest that studies combining Prazosin with effective psychotherapies might demonstrate further improvements in overall PTSD symptoms.68 Conclusions There are safe and efficacious treatments for pediatric anxiety disorders. However, there is a need to study other potential treatment options for those children and adolescents who do not successfully respond to first-line treatments. There are preliminary studies examining experimental pharmacological approaches that may lead to additional medication options. Another issue to consider is the ease of adherence to these treatments, especially to CBT. As reviewed in this article, there are promising programs that are available through computer-based
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programs. These may provide alternative treatment approaches for anxious youth. Conflicts of interest M.R. has received research funding from Eli Lilly, Pfizer, Merck, and Shine Consultancy Services, and received royalties from American Psychiatric Publishing, Inc. J.T.W. has received research funding from Pfizer. References 1. Pediatric OCD Treatment Study (POTS) Team. 2004. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder. J. Am. Med. Assoc. 292: 1969–1976. 2. Walkup, J.T., A.M. Albano, J. Piacentini, et al. 2008. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N. Engl. J. Med. 359: 2753–2766. 3. Davis, M. 2002. Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur. J. Neurosci. 16: 395–398. 4. American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: Author. 5. American Psychiatric Association. 2013. Diagnostic and Statistical Manual of Mental Health Disorders: DSM-V (5th ed.). Washington, DC: Author. 6. Ginsburg, G.S., P.C. Kendall, D. Sakolsky, et al. 2011. Remission after acute treatment in children and adolescents with anxiety disorders: findings from the CAMS. J. Consult. Clin. Psychol. 79: 806–813. 7. Silverman, W.K., A.A. Pina & C. Viswesvaran. 2008. Evidence-based psychosocial treatments for phobic and anxiety disorders in children and adolescents. J. Clin. Child Adolesc. Psychol. 37: 105–130. 8. Kendall, P.C., C.A. Settipani & C.M. Cummings. 2012. No need to worry: the promising future of child anxiety research. J. Clin. Child Adolesc. Psychol. 41: 103–115. 9. Khanna, M.S. & P.C. Kendall. 2010. Computer-assisted cognitive behavioral therapy for child anxiety: results of a randomized clinical trial. J. Consult. Clin. Psychol. 78: 737–745. 10. Spence, S.H., J.M. Holmes, S. March & O.V. Lipp. 2006. The feasibility and outcome of clinic plus Internet delivery of cognitive- behavior therapy for childhood anxiety. J. Consult. Clin. Psychol. 74: 614–621. 11. Spence, S.H., C.L. Donovan, S. March, et al. 2008. Online CBT in the treatment of child and adolescent anxiety disorders: issues in the development of BRAVE—ONLINE and two case illustrations. Behav. Cogn. Psychother. 36: 411–430. 12. March, S., S.H. Spence & C.L. Donovan. 2009. The efficacy of an Internet-based cognitive-behavioral therapy intervention for child anxiety disorders. J. Pediatr. Psychol. 34: 474–487. 13. Spence, S.H., C.L. Donovan, S. March, et al. 2011. A randomized controlled trial of online versus clinic-based CBT for adolescent anxiety. J. Consult. Clin. Psychol. 79: 629–642.
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14. Crawley, S.A., R.S. Beidas, C.L. Benjamin, et al. 2008. Treating socially phobic youth with CBT: differential outcomes and treatment considerations. Behav. Cogn. Psychother. 36: 379–389. 15. Beidel, D.C., S.M. Turner, F.R. Sallee, et al. 2007. SET-C versus fluoxetine in the treatment of childhood social phobia. J. Am. Acad. Child Adolesc. Psychiatr. 46: 1622–1632. 16. Rynn, M., A. Puliafico, C. Heleniak, et al. 2011. Advances in pharmacotherapy for pediatric anxiety disorders. Depress Anxiety 28: 76–87. 17. Mula, M., S. Pini & G.B. Cassano. 2007. The role of anticonvulsant drugs in anxiety disorders: a critical review of the evidence. J. Clin. Psychopharmacol. 27: 263–272. 18. Stein, M.B., L.N. Ravindran, N.M. Simon, et al. 2010. Levetiracetam in generalized social anxiety disorder: a doubleblind, randomized controlled trial. J. Clin. Psychiatr. 71: 627– 631. 19. Pande, A.C., J.G. Crockatt, D.E. Feltner, et al. 2003. Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am. J. Psychiatr. 160: 533–540. 20. Feltner, D.E., J.G. Crockatt, S.J. Dubovsky, et al. 2003. A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J. Clin. Psychopharmacol. 23: 240–249. 21. Greist, J.H., M. Liu-Dumaw, E. Schweizer & D. Feltner. 2011. Efficacy of pregabalin in preventing relapse in patients with generalized social anxiety disorder: results of a double-blind, placebo-controlled 26-week study. Int. Clin. Psychopharmacol. 26: 243–251. 22. Hadley, S.J., F.S. Mandel & E. Schweizer. 2012. Switching from long-term benzodiazepine therapy to pregabalin in patients with generalized anxiety disorder: a doubleblind, placebo-controlled trial. J. Psychopharmacol. 26: 461–470. 23. Levinson, D.F. & O. Devinsky. 1999. Psychiatric adverse events during vigabatrin therapy. Neurology 53: 1503. 24. Mancuso, E., A. Faro, G. Joshi & D.A. Geller. 2010. Treatment of pediatric obsessive-compulsive disorder: a review. J. Child Adolesc. Psychopharmacol. 20: 299–308. 25. Merlo, L.J., E.A. Storch, H.D. Lehmkuhl, et al. 2010. Cognitive behavioral therapy plus motivational interviewing improves outcome for pediatric obsessive-compulsive disorder: a preliminary study. Cogn. Behav. Ther. 39: 24–27. 26. Storch, E.A., N.E. Caporino, J.R. Morgan, et al. 2011. Preliminary investigation of web-camera delivered cognitivebehavioral therapy for youth with obsessive-compulsive disorder. Psychiatr. Res. 189: 407–412. 27. Storch, E.A., H.D. Lehmkuhl, E. Ricketts, et al. 2010. An open trial of intensive family based cognitive-behavioral therapy in youth with obsessive-compulsive disorder who are medication partial responders or nonresponders. J. Clin. Child Adolesc. Psychol. 39: 260–268. 28. Walker, D.L., K.J. Ressler, K.T. Lu & M. Davis. 2002. Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of D-cycloserine as assessed with fear-potentiated startle in rats. J. Neurosci. 22: 2343–2351. 29. Ledgerwood, L., R. Richardson & J. Cranney. 2003. Effects of D-cycloserine on extinction of conditioned freezing. Behav. Neurosci. 117: 341–349.
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30. Ressler, K.J., B.O. Rothbaum, L. Tannenbaum, et al. 2004. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch. Gen. Psychiatr. 61: 1136–1144. 31. Hofmann, S.G., M.H. Pollack & M.W. Otto. 2006. Augmentation treatment of psychotherapy for anxiety disorders with D-cycloserine. CNS Drug Rev. 12: 208–217. 32. Guastella, A.J., R. Richardson, P.F. Lovibond, et al. 2008. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol. Psychiatr. 63: 544–549. 33. Otto, M.W., D.F. Tolin, N.M. Simon, et al. 2010. Efficacy of d-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder. Biol. Psychiatr. 67: 365–370. 34. Storch, E.A., T.K. Murphy, W.K. Goodman, et al. 2010. A preliminary study of D-cycloserine augmentation of cognitivebehavioral therapy in pediatric obsessive-compulsive disorder. Biol. Psychiatr. 68: 1073–1076. 35. Coric, V., S. Milanovic, S. Wasylink, et al. 2003. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with obsessive-compulsive disorder and major depressive disorder. Psychopharmacology 167: 219–220. 36. Mathew, S.J., J.M. Amiel, J.D. Coplan, et al. 2005. Openlabel trial of riluzole in generalized anxiety disorder. Am. J. Psychiatr. 162: 2379–2381. 37. Coric, V., B. Kelmendi, C. Pittenger, et al. 2007. Beneficial effects of the antiglutamatergic agent riluzole in a patient diagnosed with trichotillomania. J. Clin. Psychiatr. 68: 170– 171. 38. Sasso, D.A., P.S. Kalanithi, K.V. Trueblood, et al. 2006. Beneficial effects of the glutamate-modulating agent riluzole on disordered eating and pathological skin-picking behaviors. J. Clin. Psychopharmacol. 26: 685–687. 39. Grant, P., L. Lougee, M. Hirschtritt & S.E. Swedo. 2007. An open-label trial of riluzole, a glutamate antagonist, in children with treatment-resistant obsessive-compulsive disorder. J. Child Adolesc. Psychopharmacol. 17: 761–767. 40. Grant, P., J.Y. Song & S.E. Swedo. 2010. Review of the use of the glutamate antagonist riluzole in psychiatric disorders and a description of recent use in childhood obsessivecompulsive disorder. J. Child Adolesc. Psychopharmacol. 20: 309–315. 41. Chipana, C., J. Camarasa, D. Pubill & E. Escubedo. 2008. Memantine prevents MDMA-induced neurotoxicity. Neurotoxicology 29: 179–183. 42. Stewart, S.E., E.A. Jenike, D.M. Hezel, et al. 2010. A singleblinded case-control study of memantine in severe obsessivecompulsive disorder. J. Clin. Psychopharmacol. 30: 34–39. 43. Poyurovsky, M., R. Weizman, A. Weizman & L. Koran. 2005. Memantine for treatment-resistant OCD. Am. J. Psychiatr. 162: 2191–2192. 44. Pasquini, M. & M. Biondi. 2006. Memantine augmentation for refractory obsessive-compulsive disorder. Prog. Neuropsychopharmacol. Biol. Psychiatr. 30: 1173–1175. 45. Aboujaoude, E., J.J. Barry & N. Gamel. 2009. Memantine augmentation in treatment-resistant obsessive-compulsive disorder: an open-label trial. J. Clin. Psychopharmacol. 29: 51–55.
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46. Hezel, D.M., K. Beattie & S.E. Stewart. 2009. Memantine as an augmenting agent for severe pediatric OCD. Am. J. Psychiatr. 166: 237. 47. Dorsey, S., E.C. Briggs & B.A. Woods. 2011. Cognitivebehavioral treatment for posttraumatic stress disorder in children and adolescents. Child Adolesc. Psychiatr. Clin. N. Am. 20: 255–269. 48. Cohen, J.A., A.P. Mannarino & E. Deblinger. 2006. Treating Trauma and Traumatic Grief in Children and Adolescents. New York: Guilford Press. 49. Cohen, J.A., A.P. Mannarino & L.K. Murray. 2011. Traumafocused CBT for youth who experience ongoing traumas. Child Abuse Negl. 35: 637–646. 50. Nixon, R.D., J. Sterk & A. Pearce. 2012. A randomized trial of cognitive behaviour therapy and cognitive therapy for children with posttraumatic stress disorder following single-incident trauma. J. Abnorm. Child Psychol. 40: 327–337. 51. Scheeringa, M.S., C.F. Weems, J.A. Cohen, et al. 2011. Trauma-focused cognitive-behavioral therapy for posttraumatic stress disorder in three-through six year-old children: a randomized clinical trial. J. Child Psychol. Psychiatr. 52: 853–860. 52. Cohen, J.A., A.P. Mannarino & S. Iyengar. 2011. Community treatment of posttraumatic stress disorder for children exposed to intimate partner violence: a randomized controlled trial. Arch. Pediatr. Adolesc. Med. 165: 16–21. 53. Mannarino, A.P., J.A. Cohen, E. Deblinger, et al. 2012. Trauma-focused cognitive-behavioral therapy for children: sustained impact of treatment 6 and 12 months later. Child Maltreat. 17: 231–241. 54. Kataoka, S.H., B.D. Stein, L.H. Jaycox, et al. 2003. A schoolbased mental health program for traumatized Latino immigrant children. J. Am. Acad. Child Adolesc. Psychiatr. 42: 311–318. 55. Stein, B.D., L.H. Jaycox, S.H., Kataoka, et al. 2003. A mental health intervention for schoolchildren exposed to violence: a randomized controlled trial. J. Am. Med. Assoc. 290: 603– 611. 56. The National Child Traumatic Stress Network Fact Sheet. 2012. SPARCS: Structured Psychotherapy for Adolescents Responding to Chronic Stress. 57. Weiner, D.A., A. Schneider & J.S. Lyons. 2009. Evidencebased treatments for trauma among culturally diverse foster care youth: treatment retention and outcomes. Children Youth Services Rev. 31: 1199–1205. 58. Runyon, M.K., D. Deblinger & R. Steer. 2010. Comparison of combined parent-child and parent-only cognitive behavioral treatments for offending parents and children in cases of child physical abuse. Child Fam. Behav. Ther. 32: 196–218. 59. Cohen, J.A., A.P. Mannarino, J.M. Perel & V. Staron. 2007. A pilot randomized controlled trial of combined traumafocused CBT and sertraline for childhood PTSD symptoms. J. Am. Acad. Child Adolesc. Psychiatr. 46: 811–819. 60. Poundja, J., S. Sanche, J. Tremblay & A. Brunet. 2012. Trauma reactivation under the influence of propranolol: an examination of clinical predictors. Eur. J. Psychotraumatol. Epub 2012 Feb 14. doi: 10.3402/ejpt.v3i0.15470.
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61. Nugent, N.R., N.C. Christopher, J.P. Crow, et al. 2010. The efficacy of early propranolol administration at reducing PTSD symptoms in pediatric injury patients: a pilot study. J. Trauma. Stress 23: 282–287. 62. Sharp, S., C. Thomas, L. Rosenberg & M. Rosenberg. 2010. Meyer Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J. Trauma 68: 193–197. 63. Pitman, R.K., K.M. Sanders, R.M. Zusman, et al. 2002. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatr. 51: 189–192. 64. Vaiva, G., F. Ducrocq, K. Jezequel, et al. 2003. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatr. 54: 947– 949.
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65. Taylor, F. & L. Cahill. 2002. Propranolol for reemergent posttraumatic stress disorder following an event of retraumatization: a case study. J. Trauma Stress 15: 433–437. 66. Brunet, A., S.P. Orr, J. Tremblay, et al. 2008. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42: 503–506. 67. Bell, J. 2008. Propranolol, post-traumatic stress disorder and narrative identity. J. Med. Ethics 34: e23. 68. Raskind, M.A., K. Peterson & T. Williams. 2013. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am. J. Psychiatr. 170: 1003–1010.
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A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: Childhood Onset Developmental Disorders
Treatment of pediatric anxiety disorders Amy Rapp,1 Alice Dodds,2 John T. Walkup,3 and Moira Rynn1 1 3
New York State Psychiatric Institute, New York, New York. 2 Drexel University College of Medicine, Philadelphia, Pennsylvania. Weill Cornell Medical College and NewYork–Presbyterian Hospital, New York, New York
Address for correspondence: Moira Rynn, New York State Psychiatric Institute, 1051 Riverside Drive, Box 74, New York, NY 10032. [email protected]
This article provides a brief review of the current available data concerning present treatment and potential new treatment advances for pediatric anxiety disorders, such as generalized anxiety disorder, separation anxiety disorder, social phobia, obsessive–compulsive disorder, and posttraumatic stress disorder. Disorder-specific treatment methods and innovations, particularly computer-assisted methods of delivery for cognitive behavioral therapy (CBT) will be reviewed. Additionally, the paper will discuss novel psychopharmacological compounds (e.g., d-cycloserine, riluzole, memantine, and anticonvulsant medications). Available evidence for the efficacy of novel medication strategies in adult studies and implications for their use in pediatrics will be discussed. Keywords: cognitive behavioral therapy; pharmacotherapy; pediatric; anxiety
Introduction This article will briefly review both cognitive behavioral therapy (CBT) and psychopharmacological treatments for youth anxiety disorders, with a focus on emerging treatment approaches. Thus, for CBT we will highlight interventions that utilize a group format and/or new methods of treatment dissemination, as well as considerations for partial or nonresponders to first-line treatments. Currently, cognitive behavioral therapy and selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment for pediatric anxiety disorders. Yet it is estimated that about 20–35% of patients who receive these treatments show little benefit.1,2 Therefore, research continues to be focused on developing additional treatments to either replace or augment our current treatment paradigms. Many of the novel medication treatments target the N-methyl-d-aspartate (NMDA) system, which has been implicated in emotional learning and fear extinction.3 In this article, we will explore some of the current literature on new potential compounds for the treatment of pediatric anxiety disorders; these include d-cylcoserine, N-acetylcysteine, memantine, riluzole, anticonvulsant medications, and propranolol.
Please note that the anxiety studies reviewed in this article used the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV criteria.4 Childhood anxiety disorders appear in DSM V within the chapters that discuss similar disorders found in adults. However, obsessive–compulsive disorder (OCD) is now listed in the category “OCD and Related Disorders” and posttraumatic stress disorder (PTSD) is now under the category “Trauma- and Stressor-Related Disorders” with developmentally sensitive criteria thresholds.5 Generalized anxiety disorder, social phobia, and separation anxiety disorder
Combination treatment (CBT plus SSRI) The Child/Adolescent Anxiety Multimodal Study (CAMS) remains the largest pediatric anxiety randomized clinical trial (RCT).2 This study compared the efficacy of Coping Cat (the manual-based CBT intervention) alone, sertraline alone, pill placebo, and the combination CBT and sertraline treatment, in 488 children and adolescents with a primary diagnosis of separation anxiety disorder (SAD), social phobia (SoP), and/or generalized anxiety disorder (GAD). All treatments were significantly superior to placebo. However, combination treatment led to significantly higher response rates compared to CBT doi: 10.1111/nyas.12318
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alone, sertraline alone, or pill placebo (81% versus 60% versus 55% versus 24%, respectively). Response rates for CBT alone and sertraline alone were not significantly different. Restlessness, fatigue, sedation, and insomnia were reported more often by participants receiving sertraline than those receiving CBT. No suicidal attempts were reported. Five participants (3.6%) receiving CBT alone and five participants receiving combination treatment (3.6%) reported suicidal ideation (P = ns). Ginsburg et al.6 found similar results when examining remission rates in the CAMS study; all treatments remained superior to placebo, with the combination treatment leading to significantly higher remission rates than sertraline alone, CBT alone, or pill placebo (46– 68% versus 34–46% versus 20–46% versus 15–27%, respectively). Both sertraline alone and CBT alone led to significantly higher remission rates than pill placebo, but rates were not different from each other. Factors associated with remission were absence of comorbid internalizing disorders, absence of SoP, lower baseline anxiety severity, nonminority status, and younger age. In fact, participants with SoP at baseline were significantly less likely to achieve remission across treatment conditions compared to those without SoP. Additionally, the majority of participants had some residual anxiety symptoms after 12 weeks of treatment. However, this large anxiety trial confirms that the field has three efficacious treatment approaches: CBT, SSRI, and the combination of these two treatments. There is a need to do further research related to additional comorbid diagnoses and outcome. Presently, there is an ongoing follow up study to the CAMs sample that should provide helpful information on long-term outcomes. Given that CBT is a well-established and efficacious treatment for this anxiety triad in youth, there remains the challenge of access to this specialized treatment.2,6,7 A new area of treatment that is emerging is computer-based and computer-assisted CBT interventions, which increase accessibility, allow for additional privacy, and are cost effective.8 Below we have highlighted two computer-based and computer-assisted interventions for the anxiety triad. Camp Cope-A-Lot (CCAL). CCAL is a 12-session intervention for youth aged 7–13 years that have an anxiety disorder(s) that can be implemented
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by providers without previous CBT training. The computer-assisted program includes a therapist, or coach, in addition to computerized sessions. CCAL was compared to individual CBT (ICBT) and a computer-linked education, support, and attention (CESA) condition in one RCT (N = 49) by Khanna and Kendall.9 At posttreatment, 70% of participants randomized to ICBT and 81% of participants randomized to CCAL no longer carried principal diagnoses, compared to 19% of those assigned to CESA. Independent evaluator–rated severity and functioning also indicated gains over time. Ratings of satisfaction, therapist adherence, flexibility, and alliance were also obtained. Therapist adherence was significantly greater for CCAL (t (40) = 2.1, P < 0.05) and CESA (t (33) = 3.2, P < 0.01) compared to ICBT. Therapeutic alliance was consistently rated across conditions; however, ratings of therapist flexibility were greater for ICBT (F2,39 = 10.9, P < 0.01) than for CCAL (t (38) = 3.5, P < 0.01) and CESA (t (33) = 2.6, P < 0.05). Parent ratings of treatment satisfaction did not differ significantly across treatment assignments; however, child-reported satisfaction was significantly higher for both CCAL and ICBT when compared to CESA (F2,45 = 6.1, P < 0.05; F2, 45 = 3.36, P < 0.05, respectively). Results from this study indicate that children assigned to receive CCAL showed similarly significant improvement in anxiety severity and global functioning compared to ICBT. Of note, ratings of CCAL therapist adherence were greater than those for ICBT. Such findings suggest that CCAL may be a promising intervention and may reduce therapist deviation from treatment manuals commonly seen in community practice. BRAVE-ONLINE. The BRAVE-ONLINE program is an adaptation of a clinic-based CBT intervention for anxiety-disordered youth aged 7–14 years. The acronym BRAVE stands for five anxietymanagement strategies: body signs (detecting physiological symptoms of anxiety), relax (mindfulness, deep breathing, guided imagery), activate helpful thoughts (cognitive restructuring and coping self-talk), victory over fears (exposure components and problem solving), and enjoy yourself (self-reward).10 This intervention is delivered over 10 weekly sessions plus two additional sessions for skill consolidation and relapse prevention. In addition to the computerized software, the intervention also includes weekly online contact and two phone
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contacts with a therapist.11 March et al.12 compared BRAVE-ONLINE (henceforth referred to as internet-based CBT (NET)) to a waitlist condition. At posttreatment, nine of 30 youth (30%) assigned to receive NET no longer met criteria for a primary anxiety disorder compared to three of 29 (10.3%) youth in the waitlist condition, as determined by combined parent and child reports on the parent version of the Anxiety Disorders Interview Schedule (ADIS-P) and the child version of the ADIS (ADIS-C). Improved clinical outcomes in previous trials of clinic-based CBT have been reported; however, outcomes at a 6-month follow-up were consistent with previous studies (i.e., 75% of children no longer had their primary anxiety diagnosis). The authors acknowledge adherence as a limitation of postintervention gains, with only 60% of parents and 33.3% of children completing all therapy sessions at 10 weeks. In a recent RCT,13 NET was compared to an active control (clinic-based CBT) and a waitlist condition. At posttreatment, both NET and clinic-based CBT produced clinically significant improvement, as defined by CSR less than or equal to three for the primary anxiety diagnosis. Fifteen of 41 participants (36.6%) in the completer sample in the NET condition and 13 of 40 participants (32.5%) in the clinic-based CBT arm demonstrated significant improvement at posttreatment. In the waitlist condition, one of 24 participants (4.2%) demonstrated significant improvement at posttreatment. These results suggest that online CBT may have treatment potential and is worth continued study. The differences in the response rates between BRAVE and CCAL may reflect differences in the adherence and makeup of the anxiety diagnoses, with BRAVE having a higher percentage of youth suffering from SoP. Evidence suggests that the treatment response to CBT is not necessarily consistent across anxiety disorders. Youth with a principal diagnosis of SoP were shown to demonstrate a less favorable treatment outcome compared to youth with a principal diagnosis of GAD or SAD.14 Kendall et al. drew attention to common characteristics of youth with SoP who participated in the Crawley et al. study that could explain this discrepancy, including: high occurrence of comorbidity, greater degree of impairment at baseline, and older age. Other factors, such as parent psychopathology, depression comorbidity, and self-consciousness, may also contribute to limited improvement posttreatment.14 Additionally, Beidel 54
et al. showed that both fluoxetine and Social Effectiveness Therapy for Children (SET-C) are efficacious treatments for reducing social distress in adolescents with social phobia. However, SET-C appears to provide additional benefits compared to fluoxetine alone by improving social skills.15 Moreover, adding social skills training for youth with social phobia may augment treatment response.6 Behavioral activation, such as social skills training and peer exposure integrated into treatment, may facilitate the child’s use of anxiety-management skills.14 The identification of these distinctions between youth with SoP compared to those with GAD or SAD indicates the need to better understand change processes during treatment for these youth. Such insight may contribute to treatment personalization and the development of targeted augmentation strategies for partial or nonresponders.8
Experimental pharmacological approaches Presently, the first-line medication treatment of pediatric triad anxiety disorders is the SSRI class of medication. There are numerous controlled trials that support this class of medication for its efficacy and safety. Additionally, there are studies examining the potential efficacy of benzodiazepines, serotonin– norepinephrine reuptake inhibitors, and buspirone (see review by Rynn et al.16 ). With reference to new medication approaches for children and adolescents who do not respond to first-line treatment, there are few studies in the pediatric population evaluating other medication treatment options and most are in the adult population, as reviewed in this article. Anticonvulsant medications Currently, no studies have examined the use of anticonvulsants to treat pediatric anxiety disorders. It is hypothesized that anticonvulsants may treat anxiety disorders through their actions on ␥ -aminobutyric acid (GABA), one of the major inhibitory neurotransmitters in the brain.17 In an RCT of levetiracetam for the treatment of adult social anxiety disorder, Stein et al.18 did not find a significant difference in response rates between levetiracetam and placebo (41.3% versus 46.6%, respectively; P > 0.05). In contrast, RCTs of pregabalin have shown promising results in adults for the treatment of GAD,19,20 and SoP.20 Pregabalin has also been shown to decrease relapse rates in adults with SoP.21 Furthermore, research has suggested that pregabalin may reduce anxiety and withdrawal symptoms
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in adults with GAD on long-term benzodiazepine therapy.22 Across these studies, medication treatment was well-tolerated, with the major side effects including somnolence and dizziness. However, other studies on patients with epilepsy have highlighted several psychopathological side effects associated with anticonvulsant treatment, including affective disorders, aggression, and psychosis.17,23 Research by Mula et al. found that patients with a personal or family history of psychiatric disease were more likely to develop these side effects.17 Clearly, research on the use of anticonvulsants in children with anxiety disorders is needed to further elucidate their safety and efficacy even for consideration as an alternative for treatment of refractory cases. Obsessive–compulsive disorder
CBT CBT is considered a first-line treatment for OCD in youth. Exposure and response prevention (E/RP), a type of CBT that gradually implements exposure to feared stimuli under patient or therapist control, is often administered in this population.24 However, investigation of adjunctive interventions for youth with OCD receiving CBT is warranted, particularly for youth who display unwillingness to engage in treatment. One randomized trial (N = 16) assigned participants to receive CBT plus motivational interviewing (MI) or CBT plus psychoeducation (control) for up to 14 sessions over 3 weeks.25 For those randomized to receive CBT plus MI, three MI sessions took place at specific time points in the treatment during which hesitation or fears might be expected to peak (i.e., pretreatment, after completing exposure homework independently, and when participants reach the highest level of fear hierarchies). Outcome was measured by the Children’s Yale– Brown Obsessive–Compulsive Scale (CYBOCS) total score and CGI severity/improvement. Although at posttreatment, there were no significant differences in outcome measures between the two groups, significant reductions in CYBOCS scores were noted following the second MI session (mean change = 16.75, SD = 9.66) and third MI session (mean change = 21.38, SD = 9.12) compared to the same time points for youth in the control condition (mean change = 8.31, SD = 6.01; mean change = 13.13, SD = 9.01, respectively). These preliminary results suggest that incorporating MI sessions may accelerate treatment gains, thus shortening the duration of
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treatment, and have practical implications for families by minimizing the travel time and financial cost associated with treatment. As noted previously in this article, although CBT is efficacious for treating youth anxiety disorders, adherence to CBT may be challenging for some youth. Web-based adaptations may be helpful in overcoming this limitation. Computer and webbased interventions have been developed for adults with OCD, but few options exist for youth with OCD. One RCT (n = 31)26 randomized participants to receive a web-based adaptation (W-CBT) of the treatment protocol used in the Pediatric OCD Treatment Study (POTS)1 or a waitlist condition. At posttreatment, average CYBOCS reduction was greater for the W-CBT arm than the waitlist condition (56.1% versus 12.9%). Criteria for remission was met by nine of 16 participants (56%) assigned to WCBT compared to two of 15 participants (13%) assigned to the control. However, this study’s promising preliminary findings are limited by its lack of an active-control comparator arm (i.e., clinic-based CBT). Future trials of W-CBT are warranted to provide further insight into overcoming implementation challenges of this intervention, such as difficulties in establishing a therapeutic alliance. One clinical trial targeted medication partial responders or nonresponders to at least two or more trials of SSRIs and/or SSRI augmented by an atypical antipsychotic.27 Study participants (n = 30) received 14 sessions of intensive family-based CBT over 3 weeks. Parental involvement was required at all sessions. Significant differences in CYBOCS severity were demonstrated from pre- to posttreatment (t (29) = 10.60, P < 0.001) and maintained at follow-up (t (29) = –0.13, P > 0.05). Additionally, at posttreatment, 17 of 30 participants (56.6%) were considered to have reached remission status as defined by a severity rating on the ADIS-IV-P of less than or equal to 3 and a CYBOCS total score less than or equal to 10. At the 3-month follow-up, 16 of 30 participants (53.3%) maintained remission status. These results corroborate the use of CBT as a first-line treatment for OCD and suggest that intensive family-based CBT may be particularly relevant for treatment-resistant youth.
Combination treatment The Pediatric OCD Treatment Study examined the efficacy of sertraline alone, CBT alone, and the
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combination of CBT and medication compared to placebo. Similar to the findings in CAMS, combination treatment significantly decreased symptoms of OCD on the primary outcome measure (combined, P = 0.001; sertraline, P = 0.007; and CBT, P = 0.003). When the sample was examined for those youth achieving excellent response, the combination treatment and CBT alone were not significantly different, and medication treatment did not differ significantly from placebo. This suggests that when a child is able to engage in CBT treatment, it is reasonable to treat first with CBT alone, with the option to add an SSRI if CBT is not effective.
Experiment pharmacological treatments D-Cycloserine. Research in both animals and adults has suggested that d-cycloserine may augment the effects of CBT treatment in children and adolescents with anxiety disorders.28–33 Storch et al.34 conducted a preliminary RCT on d-cycloserine augmentation of CBT in pediatric OCD. Thirty participants were randomized to receive either d-cycloserine or placebo 1 h before CBT treatment. No significant difference was found between treatment groups. However, CBT plus dcylcoserine showed small to moderate treatment effects on primary outcome measures (d = 0.31– 0.47). Riluzole. Current research on the pathophysiology of OCD has suggested that excess glutamate, the primary excitatory neurotransmitter in the brain, may underlie OCD. Riluzole is a potent glutaminergic antagonist and therefore offers a novel therapy for targeting the overactive glutamate pathway. Open-label trials and case studies in adults with anxiety disorders have demonstrated that Riluzole is an effective treatment for OCD,35 GAD,36 trichotillomania,37 eating disorder, and skin-picking behavior.38 One open-label trial of Riluzole in six pediatric patients with treatmentresistant OCD found that four participants responded during the 12 week trial, and one participant responded after trial completion.39 Although no participants discontinued the study, two participants had elevated liver transaminases. An RCT of Riluzole in pediatric OCD has been recently completed at the National Institute of Mental Health (NIMH);40 this study includes participants with comorbid autism spectrum disorders. Preliminary tolerability results from 46 participants in56
clude two participants who developed pancreatitis while on concomitant medications and one participant with baseline steatosis who developed elevated transaminases. All three participants recovered completely once Riluzole was discontinued. Memantine. This is a noncompetitive antagonist of the NMDA receptor that is thought to protect neurons from the neurotoxic effects of glutamate.41 One single-blind study42 on memantine for the treatment of OCD in adults showed promising results. However, case studies on memantine as an augmenting agent in treating adult OCD have had mixed results.43–45 Currently, no clinical trials have examined the use of memantine in pediatric anxiety disorders. However, Hezel et al.46 described a case report of a 15-year-old female patient with OCD refractory to treatment who had a robust response to memantine, with only mild to subclinical symptoms after 1 month of treatment. She did not show any signs of relapse at her 9-month follow-up. All studies reported good tolerance to memantine. Posttraumatic stress disorder
CBT Trauma-focused CBT (TF-CBT). Evidence is most robust for trauma-focused CBT (TF-CBT) among CBT approaches for treating symptoms of PTSD in youth.47 TF-CBT is often provided to youth who have experienced past trauma; it is appropriate for youth aged 3–18 years and is generally delivered over 12–20 sessions.48 The intervention consists of nine components referred to by the acronym PRACTICE: psychoeducation, parenting skills, relaxation skills, affective modulation skills, cognitive coping skills, trauma narration and processing, in vivo mastery of trauma reminders, conjoint child– parent sessions, and enhancing safety.48 Formal exposure is a critical component of TF-CBT; however, Cohen et al.49 raised the appropriateness of exposure work for youth experiencing ongoing trauma. The authors suggest that additional considerations may need to be taken, including enhancing safety early in treatment, increasing parental engagement, and optimally focusing the trauma narration and processing, when treating this population of youth with TF-CBT. Nixon et al.50 compared TF-CBT to trauma-focused cognitive therapy (TF-CT) in a recent RCT (n = 34). The lack of an exposure component distinguishes TF-CT from TF-CBT. At
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posttreatment, both arms demonstrated reduced symptom severity, with 65% of participants in the TF-CBT arm and 56% of participants in the TF-CT arm meeting remission criteria. These results suggest that nonexposure based treatment may be a viable option for treating youth experiencing ongoing trauma. Two recently published RCTs examined effectiveness of TF-CBT. Sixty-four youth were enrolled in an RCT51 to assess the effectiveness of TF-CBT in very young children aged 3–6 years. A second RCT (N = 124) aimed to evaluate TF-CBT compared to child-centered therapy (CCT) for children with PTSD symptoms following experiences of intimate partner violence (IPV).52 In both studies, reduction in PTSD symptoms was greater in the TF-CBT arm than in the comparator arm. One follow-up study53 investigated the maintenance of TF-CBT treatment gains at 6 and 12 months posttreatment; the treatment gains were sustained at both assessment points. Finally, Dorsey et al. reviewed several CBT approaches that have a strong evidence base or are “promising practices” for the treatment of PTSD in youth.47 Three group interventions are highlighted in the following section. Cognitive–Behavioral Intervention for Trauma in Schools (CBITS). CBITS is a 10-session intervention that includes individual sessions and teacher education, as well as optional parent sessions. This school-based treatment was initially designed for youth exposed to violence in the community. However, CBITS has been adapted for youth with a range of trauma experiences (e.g., recent immigration54 ) and also for implementation in nonschool settings. Stein et al.55 conducted an RCT (N = 126) comparing CBITS to a waitlist-delayed intervention group. After 3 months, the comparator group also received CBITS. Assessments of symptoms and functioning were administered at baseline, 3 months, and 6 months. Self-reported symptoms of PTSD, as assessed using the Child PTSD Symptom Scale, were significantly lower for participants assigned to early intervention compared to the delayed intervention group at the 3-month posttreatment follow-up (8.9 versus 15.5). However, significant differences were not preserved at a 6-month follow-up after both groups received the intervention. Parent reports of psychosocial dysfunction, as assessed by the Pediatric Symptom Checklist, were also significantly re-
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duced for youth assigned to early intervention (12.5 versus 16.5). Similarly to child reports of symptoms at 6 months, parent reports of psychosocial dysfunction were not significantly different between early intervention and delayed intervention groups (9.4 versus 8.9). Teacher reports of classroom behavior, as assessed by the Teacher–Child Rating Scale, revealed no significant differences between early intervention and delayed intervention groups at both 3 and 6 months. CBITS is a promising treatment model for implementation in school and community settings. Structured Psychotherapy for Adolescents Responding to Chronic Stress (SPARCS). SPARCS is a present-focused, developmentally sensitive intervention delivered over 16 sessions for youth aged 12–21 years.56 It implements common elements of CBT (excluding an exposure component) and Dialectic Behavioral Therapy to address the needs of youth with complex trauma histories and who have been exposed to chronic interpersonal trauma. Weiner et al.57 aimed to study the cross-cultural effectiveness of three treatments: SPARCS, Child– Parent Psychotherapy, and TF-CBT. In this pilot study (N = 133), 33 youth aged 13–21 years were enrolled to receive SPARCS. The intervention improved functioning in multiple domains across ethnic subgroups and reduced problems as rated by the Child and Adolescent Needs and Strengths tool in African-American youth. Combined Parent–Child Cognitive-Behavioral Approach for Children and Families At-Risk for Child Physical Abuse (CPC-CBT). CPC-CBT differs from existing interventions for families at risk for physical child abuse since it includes pediatric PTSD symptoms as a primary treatment focus. The treatment utilizes a 16-week multifamily group design of 2-h sessions involving concurrent parent and child interventions, followed by parent–child joint sessions. One RCT (N = 75) compared CPC-CBT to parent-only CBT.58 Children included in treatment (i.e., assigned to the CPC-CBT arm) experienced greater improvement in PTSD symptoms compared to children who were not included in treatment. Furthermore, parents assigned to the CPC-CBT arm reported greater improvements in positive parenting, as assessed by the Alabama Parenting Questionnaire, compared to parent-only treatment.
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Combination treatment Cohen et al.59 compared TF-CBT plus sertraline to TF-CBT plus pill placebo in a pilot study for the treatment of PTSD in sexually abused children. The sample consisted of 24 female participants aged 10–17 years and diagnosed with PTSD (92%) or posttraumatic stress syndrome. Both groups experienced a significant reduction in PTSD symptoms, without any significant difference in response across treatments. Experimental pharmacological treatments Propranolol has been studied as a potential treatment for PTSD. By blocking the adrenergic system, propanolol may inhibit memory consolidation.60 Only two studies have explored the use of propranolol in pediatric anxiety, and neither found significant results. Nugent et al.61 conducted an RCT on the use of propranolol in pediatric injury victims. Twenty-nine participants started on propranolol or placebo within 12 h of a traumatic event, and then assessed for PTSD symptoms 6 weeks later. At follow-up, only one participant (4%) met criteria for PTSD, and 11 (42%) met criteria for partial PTSD. No significant difference was found between treatment groups for diagnostic status, PTSD symptoms, or heart rate during trauma narrative. However, there was a significant trend for elevated PTSD symptoms in adherent girls in the propranolol group compared to the placebo group (R2 = 0.44, P = 0.05). Also, there was a nonsignificant trend for decreased PTSD symptoms in adherent boys in the propranolol group compared to the placebo group (R2 = 0.32, P = 0.09). Although history of a prior trauma did not predict current PTSD symptomatology, it is intriguing that participants in the propranolol group who had fewer PTSD symptoms were often male without a history of prior trauma, and those who had more PTSD symptoms were often female with a history of trauma. These findings highlight that gender and prior trauma history may influence patient response to early propranolol intervention. One retrospective review by Sharp et al.62 found no difference in the prevalence of acute stress disorder among pediatric burn victims treated with propranolol compared to those who didn’t receive propranolol (8% versus 5%, respectively). One pilot RCT (N = 41) has been done on the use of propranolol (40 mg, four times daily) for 58
the treatment of adult PTSD.63 Treatment began within 6 h of the traumatic event. At 1 month, mean PTSD score, as measured by the ClinicianAdministered PTSD Scale (CAPS), did not differ between treatment groups. Rates of PTSD at 1 month were lower in the propranolol group compared to placebo but failed to reach statistical significance (18% versus 30%, P = 0.39). These nonsignificant results may be secondary to an outlier in the propranolol group that had a mean CAPS score that was five standard deviations greater than the mean for that group. At the 3-month follow-up, the propranolol-treated group showed decreased physiological responses to traumatic imagery compared to the placebo group (0% versus 43%, P = 0.04), but failed to show a significant difference in PTSD rates (11% versus 13%, P = 0.62). An open-label trial64 and one case report65 support the use of propranolol in preventing as well as treating adult PTSD. One RCT (N = 19)66 and three open-label trials60 on the administration of propranolol during trauma reactivation sessions have also shown positive results in adults. Despite these positive findings, using propranolol to prevent and treat adult PTSD remains controversial because of the medication’s effects on personal memory.67 Prazosin is effective for combat-related PTSD with trauma nightmares in active-duty soldiers.68 Raskind et al. showed that Prazosin was effective for all three primary outcome measures: combat-related trauma nightmares, sleep quality, and global status. However, substantial residual symptoms suggest that studies combining Prazosin with effective psychotherapies might demonstrate further improvements in overall PTSD symptoms.68 Conclusions There are safe and efficacious treatments for pediatric anxiety disorders. However, there is a need to study other potential treatment options for those children and adolescents who do not successfully respond to first-line treatments. There are preliminary studies examining experimental pharmacological approaches that may lead to additional medication options. Another issue to consider is the ease of adherence to these treatments, especially to CBT. As reviewed in this article, there are promising programs that are available through computer-based
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programs. These may provide alternative treatment approaches for anxious youth. Conflicts of interest M.R. has received research funding from Eli Lilly, Pfizer, Merck, and Shine Consultancy Services, and received royalties from American Psychiatric Publishing, Inc. J.T.W. has received research funding from Pfizer. References 1. Pediatric OCD Treatment Study (POTS) Team. 2004. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder. J. Am. Med. Assoc. 292: 1969–1976. 2. Walkup, J.T., A.M. Albano, J. Piacentini, et al. 2008. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N. Engl. J. Med. 359: 2753–2766. 3. Davis, M. 2002. Role of NMDA receptors and MAP kinase in the amygdala in extinction of fear: clinical implications for exposure therapy. Eur. J. Neurosci. 16: 395–398. 4. American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: Author. 5. American Psychiatric Association. 2013. Diagnostic and Statistical Manual of Mental Health Disorders: DSM-V (5th ed.). Washington, DC: Author. 6. Ginsburg, G.S., P.C. Kendall, D. Sakolsky, et al. 2011. Remission after acute treatment in children and adolescents with anxiety disorders: findings from the CAMS. J. Consult. Clin. Psychol. 79: 806–813. 7. Silverman, W.K., A.A. Pina & C. Viswesvaran. 2008. Evidence-based psychosocial treatments for phobic and anxiety disorders in children and adolescents. J. Clin. Child Adolesc. Psychol. 37: 105–130. 8. Kendall, P.C., C.A. Settipani & C.M. Cummings. 2012. No need to worry: the promising future of child anxiety research. J. Clin. Child Adolesc. Psychol. 41: 103–115. 9. Khanna, M.S. & P.C. Kendall. 2010. Computer-assisted cognitive behavioral therapy for child anxiety: results of a randomized clinical trial. J. Consult. Clin. Psychol. 78: 737–745. 10. Spence, S.H., J.M. Holmes, S. March & O.V. Lipp. 2006. The feasibility and outcome of clinic plus Internet delivery of cognitive- behavior therapy for childhood anxiety. J. Consult. Clin. Psychol. 74: 614–621. 11. Spence, S.H., C.L. Donovan, S. March, et al. 2008. Online CBT in the treatment of child and adolescent anxiety disorders: issues in the development of BRAVE—ONLINE and two case illustrations. Behav. Cogn. Psychother. 36: 411–430. 12. March, S., S.H. Spence & C.L. Donovan. 2009. The efficacy of an Internet-based cognitive-behavioral therapy intervention for child anxiety disorders. J. Pediatr. Psychol. 34: 474–487. 13. Spence, S.H., C.L. Donovan, S. March, et al. 2011. A randomized controlled trial of online versus clinic-based CBT for adolescent anxiety. J. Consult. Clin. Psychol. 79: 629–642.
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46. Hezel, D.M., K. Beattie & S.E. Stewart. 2009. Memantine as an augmenting agent for severe pediatric OCD. Am. J. Psychiatr. 166: 237. 47. Dorsey, S., E.C. Briggs & B.A. Woods. 2011. Cognitivebehavioral treatment for posttraumatic stress disorder in children and adolescents. Child Adolesc. Psychiatr. Clin. N. Am. 20: 255–269. 48. Cohen, J.A., A.P. Mannarino & E. Deblinger. 2006. Treating Trauma and Traumatic Grief in Children and Adolescents. New York: Guilford Press. 49. Cohen, J.A., A.P. Mannarino & L.K. Murray. 2011. Traumafocused CBT for youth who experience ongoing traumas. Child Abuse Negl. 35: 637–646. 50. Nixon, R.D., J. Sterk & A. Pearce. 2012. A randomized trial of cognitive behaviour therapy and cognitive therapy for children with posttraumatic stress disorder following single-incident trauma. J. Abnorm. Child Psychol. 40: 327–337. 51. Scheeringa, M.S., C.F. Weems, J.A. Cohen, et al. 2011. Trauma-focused cognitive-behavioral therapy for posttraumatic stress disorder in three-through six year-old children: a randomized clinical trial. J. Child Psychol. Psychiatr. 52: 853–860. 52. Cohen, J.A., A.P. Mannarino & S. Iyengar. 2011. Community treatment of posttraumatic stress disorder for children exposed to intimate partner violence: a randomized controlled trial. Arch. Pediatr. Adolesc. Med. 165: 16–21. 53. Mannarino, A.P., J.A. Cohen, E. Deblinger, et al. 2012. Trauma-focused cognitive-behavioral therapy for children: sustained impact of treatment 6 and 12 months later. Child Maltreat. 17: 231–241. 54. Kataoka, S.H., B.D. Stein, L.H. Jaycox, et al. 2003. A schoolbased mental health program for traumatized Latino immigrant children. J. Am. Acad. Child Adolesc. Psychiatr. 42: 311–318. 55. Stein, B.D., L.H. Jaycox, S.H., Kataoka, et al. 2003. A mental health intervention for schoolchildren exposed to violence: a randomized controlled trial. J. Am. Med. Assoc. 290: 603– 611. 56. The National Child Traumatic Stress Network Fact Sheet. 2012. SPARCS: Structured Psychotherapy for Adolescents Responding to Chronic Stress. 57. Weiner, D.A., A. Schneider & J.S. Lyons. 2009. Evidencebased treatments for trauma among culturally diverse foster care youth: treatment retention and outcomes. Children Youth Services Rev. 31: 1199–1205. 58. Runyon, M.K., D. Deblinger & R. Steer. 2010. Comparison of combined parent-child and parent-only cognitive behavioral treatments for offending parents and children in cases of child physical abuse. Child Fam. Behav. Ther. 32: 196–218. 59. Cohen, J.A., A.P. Mannarino, J.M. Perel & V. Staron. 2007. A pilot randomized controlled trial of combined traumafocused CBT and sertraline for childhood PTSD symptoms. J. Am. Acad. Child Adolesc. Psychiatr. 46: 811–819. 60. Poundja, J., S. Sanche, J. Tremblay & A. Brunet. 2012. Trauma reactivation under the influence of propranolol: an examination of clinical predictors. Eur. J. Psychotraumatol. Epub 2012 Feb 14. doi: 10.3402/ejpt.v3i0.15470.
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61. Nugent, N.R., N.C. Christopher, J.P. Crow, et al. 2010. The efficacy of early propranolol administration at reducing PTSD symptoms in pediatric injury patients: a pilot study. J. Trauma. Stress 23: 282–287. 62. Sharp, S., C. Thomas, L. Rosenberg & M. Rosenberg. 2010. Meyer Propranolol does not reduce risk for acute stress disorder in pediatric burn trauma. J. Trauma 68: 193–197. 63. Pitman, R.K., K.M. Sanders, R.M. Zusman, et al. 2002. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol. Psychiatr. 51: 189–192. 64. Vaiva, G., F. Ducrocq, K. Jezequel, et al. 2003. Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol. Psychiatr. 54: 947– 949.
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65. Taylor, F. & L. Cahill. 2002. Propranolol for reemergent posttraumatic stress disorder following an event of retraumatization: a case study. J. Trauma Stress 15: 433–437. 66. Brunet, A., S.P. Orr, J. Tremblay, et al. 2008. Effect of post-retrieval propranolol on psychophysiologic responding during subsequent script-driven traumatic imagery in post-traumatic stress disorder. J. Psychiatr. Res. 42: 503–506. 67. Bell, J. 2008. Propranolol, post-traumatic stress disorder and narrative identity. J. Med. Ethics 34: e23. 68. Raskind, M.A., K. Peterson & T. Williams. 2013. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am. J. Psychiatr. 170: 1003–1010.
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