Guidelines for Group Presentation for Evidence-Based Literature

profilebella31!
Article1.pdf

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder A Randomized Clinical Trial Jeffrey J. Wood, PhD; Philip C. Kendall, PhD; Karen S. Wood, PhD; Connor M. Kerns, PhD; Michael Seltzer, PhD; Brent J. Small, PhD; Adam B. Lewin, PhD; Eric A. Storch, PhD

IMPORTANCE Anxiety is common among youth with autism spectrum disorder (ASD), often interfering with adaptive functioning. Psychological therapies are commonly used to treat school-aged youth with ASD; their efficacy has not been established.

OBJECTIVE To compare the relative efficacy of 2 cognitive behavioral therapy (CBT) programs and treatment as usual (TAU) to assess treatment outcomes on maladaptive and interfering anxiety in children with ASD. The secondary objectives were to assess treatment outcomes on positive response, ASD symptom severity, and anxiety-associated adaptive functioning.

DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial began recruitment in April 2014 at 3 universities in US cities. A volunteer sample of children (7-13 years) with ASD and maladaptive and interfering anxiety was randomized to standard-of-practice CBT, CBT adapted for ASD, or TAU. Independent evaluators were blinded to groupings. Data were collected through January 2017 and analyzed from December 2018 to February 2019.

INTERVENTIONS The main features of standard-of-practice CBT were affect recognition, reappraisal, modeling/rehearsal, in vivo exposure tasks, and reinforcement. The CBT intervention adapted for ASD was similar but also addressed social communication and self-regulation challenges with perspective-taking training and behavior-analytic techniques.

MAIN OUTCOMES AND MEASURES The primary outcome measure per a priori hypotheses was the Pediatric Anxiety Rating Scale. Secondary outcomes included treatment response on the Clinical Global Impressions–Improvement scale and checklist measures.

RESULTS Of 214 children initially enrolled, 167 were randomized, 145 completed treatment, and 22 discontinued participation. Those who were not randomized failed to meet eligibility criteria (eg, confirmed ASD). There was no significant difference in discontinuation rates across conditions. Randomized children had a mean (SD) age of 9.9 (1.8) years; 34 were female (20.5%). The CBT program adapted for ASD outperformed standard-of-practice CBT (mean [SD] Pediatric Anxiety Rating Scale score, 2.13 [0.91] [95% CI, 1.91-2.36] vs 2.43 [0.70] [95% CI, 2.25-2.62]; P = .04) and TAU (2.93 [0.59] [95% CI, 2.63-3.22]; P < .001). The CBT adapted for ASD also outperformed standard-of-practice CBT and TAU on parent-reported scales of internalizing symptoms (estimated group mean differences: adapted vs standard-of-practice CBT, −0.097 [95% CI, −0.172 to −0.023], P = .01; adapted CBT vs TAU, −0.126 [95% CI, −0.243 to −0.010]; P = .04), ASD-associated social-communication symptoms (estimated group mean difference: adapted vs standard-of-practice CBT, −0.115 [95% CI, −0223 to −0.007]; P = .04; adapted CBT vs TAU: −0.235 [95% CI,−0.406 to −0.065]; P = .01); and anxiety-associated social functioning (estimated group mean difference: adapted vs standard-of-practice CBT, −0.160 [95% CI, −0.307 to −0.013]; P = .04; adapted CBT vs TAU: −0.284 [95% CI, −0.515 to −0.053]; P = .02). Both CBT conditions achieved higher rates of positive treatment response than TAU (BIACA, 61 of 66 [92.4%]; Coping Cat, 47 of 58 [81.0%]; TAU, 2 of 18 [11.1%]; P < .001 for each comparison).

CONCLUSIONS AND RELEVANCE In this study, CBT was efficacious for children with ASD and interfering anxiety, and an adapted CBT approach showed additional advantages. It is recommended that clinicians providing psychological treatments to school-aged children with ASD consider developing CBT expertise.

TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02028247

JAMA Psychiatry. 2020;77(5):474-483. doi:10.1001/jamapsychiatry.2019.4160 Published online November 22, 2019.

Supplemental content

Author Affiliations: Department of Education, University of California, Los Angeles, Los Angeles (J. J. Wood, Seltzer); Department of Psychiatry, University of California, Los Angeles, Los Angeles (J. J. Wood, K. S. Wood); Department of Psychology, Temple University, Philadelphia, Pennsylvania (Kendall); Department of Psychology, University of British Columbia, Vancouver, British Columbia, Canada (Kerns); University of South Florida School of Aging Studies, Tampa (Small); Departments of Pediatrics and Psychiatry, University of South Florida, Tampa (Lewin); Baylor College of Medicine, Houston, Texas (Storch).

Corresponding Author: Jeffrey J. Wood, PhD, University of California, Los Angeles, 405 Hilgard Ave, 3132 Moore Hall, Los Angeles, CA 90095 ([email protected]) and Philip C. Kendall, PhD, Department of Psychology, Temple University, 1701 N 13th St, Philadelphia, PA 19122 ([email protected]).

Research

JAMA Psychiatry | Original Investigation

474 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

A utism spectrum disorder (ASD) affects about 1 of 59school-aged youth in the United States.1 Maladaptiveand interfering anxiety is common among youth with ASD and associated with functional impairment above and be- yond the presence of ASD.2 In addition to common childhood fears (eg, separation, generalized anxiety), maladaptive dis- tinctive fears (eg, fears of beards, specific sounds, minor change) are also common.3,4 Higher levels of child anxiety are associated with greater difficulties with school adjustment, so- cial skills, friendship, loneliness, self-injurious behavior, and family conflict in youth with and without ASD.5-8

Studies of youth with ASD in the United States have esti- mated that psychological therapy (often referred to as psycho- therapy) is among the most frequently used mental health ser- vices for youth with ASD, with as many as 23% to 43% of youth accessing this type of treatment.9,10 Several small random- ized clinical trials using wait-list or usual-care control condi- tions suggest that a specific form of psychotherapy, cognitive behavioral therapy (CBT), may be beneficial for school-aged youth with ASD and anxiety.11-18 However, no psychological or pharmacological treatments for anxiety in school-aged chil- dren with ASD meet contemporary evidentiary standards19

as efficacious or well-established. Several CBT programs have been adapted for the charac-

teristics of ASD.11-15 The rationale for adapted CBT programs for youth with ASD is multifaceted: (1) achieving generaliz- able symptom change in youth with ASD has been a chal- lenge in some treatment programs,20 (2) contextual factors that cause anxiety (eg, social communication challenges, ASD- associated stressors) likely necessitate a psychological treat- ment that addresses these contextual factors,14 and (3) youth with ASD may benefit from more parental involvement in psy- chological treatment than is typical in standard-of-practice CBT.21 Other CBT programs have been developed for typi- cally developing youth but also tested for youth with ASD.16,17

These initial studies suggest that CBT is a promising modality for treating anxiety in youth with ASD, but study limitations (eg, small samples, use of wait-list control arms) preclude efficacy conclusions.18 It is unknown whether adapted CBT differs from standard-of-practice CBT in its effects on youth outcomes.

The present study evaluated the efficacy of 2 versions of CBT (adapted CBT and standard-of-practice CBT) for anxiety in youth with ASD using a study design capable of testing relative treatment efficacy with sufficient statistical power, and assessed the effect of CBT on anxiety symptoms, ASD symptom severity, and adaptive functioning. It was hypoth- esized that (1) children randomized to CBT would exhibit greater improvement in these domains relative to children randomized to treatment as usual (TAU) and (2) CBT adapted for youth with ASD would show advantages over standard- of-practice CBT.

Methods The study protocol is included in Supplement 1 and has been summarized elsewhere.22 Details about the sample and a brief

description of the measures, eligibility criteria, and treat- ment conditions are presented. The Consolidated Standards of Reporting Trials guidelines were followed.

Participants Participants were a volunteer sample of children with ASD and maladaptive and interfering anxiety; the eligible age range was 7 to 13 years. Three universities in major US metropolitan areas (Los Angeles, California; Tampa, Florida; and Philadelphia, Pennsylvania) served as data collection sites. A power analy- sis was conducted to determine target sample size.22

This study was approved by university-based institu- tional review boards at each site (University of California, Los Angeles general institutional review board, University of South Florida institutional review board, and Temple Univer- sity’s Human Research Protection Program). Parents gave writ- ten informed consent and children gave assent to participate after receiving a complete description of the study.

Telephone contact was initiated by parents to the study coordinator, and an initial screening was conducted. Fami- lies received $75 for participating in the assessments. Recruit- ment began April 2014, and final data were collected in Janu- ary 2017, coinciding with the grant support period.

Eligibility criteria included having a clinical diagnosis of ASD confirmed by the study’s clinical research evaluation, an IQ of 70 or more points (±SEM), and anxiety (as defined by a Pediatric Anxiety Rating Scale [PARS] total score of ≥14 points, which corresponds with maladaptive and interfering anxiety)23,24 (complete criteria are in the protocol [Supple- ment 1]). The site principal investigator determined eligibil- ity status at screening. Participants were notified of their eligibility status by the study coordinator and, if eligible, pro- ceeded to complete secondary outcome measures.

Interventions Participants were randomized using a computer-generated algorithm in a parallel study design with a 4.5:4.5:1 ratio to (1) standard-of-practice CBT (termed the Coping Cat program),25

(2) CBT adapted for ASD (the Behavioral Interventions for Anxi- ety in Children with Autism [BIACA] program),14 or (3) TAU. Randomization was conducted by the study statistician (B.J.S.),

Key Points Question Does cognitive behavioral therapy (CBT) reduce anxiety symptoms in children with autism spectrum disorder (ASD) and maladaptive and interfering anxiety?

Findings In this randomized clinical trial of 167 children with ASD and maladaptive and interfering anxiety, 2 variants of CBT were compared with a treatment-as-usual condition. Cognitive behavioral therapy designed for children with ASD yielded significantly lower anxiety scores on the primary outcome measure than standard-of-practice CBT and treatment as usual; both types of CBT yielded higher rates of positive treatment response than treatment as usual.

Meaning Per this analysis, CBT is efficacious for the treatment of maladaptive and interfering anxiety in children with ASD.

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder Original Investigation Research

jamapsychiatry.com (Reprinted) JAMA Psychiatry May 2020 Volume 77, Number 5 475

© 2019 American Medical Association. All rights reserved.

who had no contact with participants. The statistician in- formed the study coordinator of the random assignment for each participant, who subsequently notified participants. Fami- lies were not informed of study hypotheses.

Therapists (19 graduate students and postdoctoral fellows) received 8 hours of training in the treatment proto- cols, read the treatment manuals, and attended weekly super- vision sessions with a licensed psychologist. Children were assigned to an available therapist based on availability. The same therapists were trained in and provided both CBT treatments. Both CBT treatments have been desc ribed extensively elsewhere12-15,22,26-29 and in the study protocol (Supplement 1).

Standard-of-Practice CBT Participants received 16 weekly 60-minute sessions of the Coping Cat program, which was found to be effective in trials of typically developing youth aged 7 to 13 years.26-29 The main features are (1) recognizing anxious feelings and somatic reac- tions to anxiety, (2) identifying cognition in anxiety-provoking situations (eg, expectations of threat), (3) developing a plan to cope (eg, reappraisal), (4) imaginal and in vivo exposure tasks, and (5) self-reinforcement for effort. The treatment uses mod- eling, role-play, and contingent reinforcement. Specific home- work tasks are assigned. Parent involvement in the child’s treatment includes a regular 15-minute check-in at the start of each session and 2 meetings with the therapist.

Adapted CBT (BIACA) Like Coping Cat, BIACA uses CBT strategies, such as reap- praisal and exposure. The BIACA program differs from Coping Cat in the following ways: (1) children receive 16 weekly 90-minute sessions (split evenly between children and par- ents) to facilitate parent engagement; (2) BIACA uses a modu- lar format guided by an algorithm to personalize treatment, given the multifaceted clinical presentations in ASD; (3) chil- dren’s disruptive behavior is addressed as needed with ante- cedent and incentive-based practices to reduce the influence of aggression and noncompliance on treatment engagement; (4) children are taught social engagement skills as needed (eg, playdate hosting, joining peers at play) to facilitate suc- cessful peer-oriented exposure-therapy assignments; (5) the children’s special interests are treated as an asset and incor- porated into treatment to promote engagement; (6) target be- haviors are reinforced with a comprehensive reward system at home and, when relevant, in school to promote motivation and treatment engagement. Further clinical description of BIACA and its treatment algorithm has been published elsewhere.30-34 An app with training and clinician guidance in- corporating the algorithm has been developed for BIACA and associated practices and is available free of charge at https:// meya.ucla.edu.

Treatment as Usual Participants in the TAU arm continued in their usual services and were provided with referrals. No specific treatment rec- ommendations were given. Families were permitted to choose or maintain any treatment approach for 4 months. After TAU,

for ethical reasons, families were offered their choice of either CBT condition if their children were still symptomatic.

Therapist Fidelity Therapists’ adherence to the interventions was monitored through session audio recordings. A random selection of ses- sions (92 for BIACA and 70 for Coping Cat) was coded for fidelity by the principal investigators (P.C.K. and J.J.W.) and trained research assistants. Coders noted the presence or absence of required topics for each session. There was ad- herence to 97% and 96% of the required topics in BIACA and Coping Cat sessions, respectively. A second coder rated 14.3% of the coded tapes to assess interrater reliability (intraclass correlations: BIACA, 0.85; Coping Cat, 1.00).

Measures Assessments were conducted by trained, research-certified independent evaluators blinded to treatment condition. Mea- sures were selected based on strong psychometric profiles for youth with ASD. The ASD diagnoses were assigned by an in- dependent evaluator using the Childhood Autism Rating Scale Second Edition–High Functioning Version and the Autism Di- agnostic Observation Schedule–2 (ADOS-2). Eligible children met criteria for ASD on algorithm scores from both assess- ments. A second independent evaluator, unaware of the origi- nal scores, independently rated 18 Autism Diagnostic Obser- vation Schedule–2 and 18 Childhood Autism Rating Scale interviews selected randomly, with 100% agreement for meet- ing ASD criteria on both measures. Each participant’s IQ score was assessed using the Wechsler Intelligence Scale for Children– IV; estimated full-scale IQ was based on the Vocabulary and Matrix Reasoning subscales.

The primary outcome measure was the PARS,35 an inde- pendent evaluator–administered scale assessing anxiety symp- toms and associated severity and impairment over the past week. The PARS Severity Scale item scores range from 0 to 5 points, with higher scores reflecting more maladaptive and in- terfering anxiety; a mean of scores on the 7 items was calcu- lated. The PARS, which is psychometrically sound and treat- ment sensitive in samples of children with ASD,12-15,36 was administered at baseline, midtreatment (session or week 8), and after treatment (within 1 week of the last session). The me- dian interrater reliability across assessments (r) was 0.88. The Clinical Global Impression–Improvement scale37 was rated by the independent evaluator after the postbaseline PARS inter- views. This scale is a 7-point rating of treatment response rang- ing from 1 (very much improved) to 7 (very much worse). A rat- ing of 1 or 2 designated a positive treatment response.

Secondary outcome rating-scale measures were com- pleted by parents, including the Child Behavior Checklist, Social Responsiveness Scale–2, and the Child Anxiety Impact Scale (CAIS).38 Higher scores on all outcome measures reflect more symptoms or impairment; scores are the mean item value of each scale. Secondary outcome measures were adminis- tered before and after treatment. Additional detail about these measures is provided in the eMethods in Supplement 2. The Service Assessment for Children and Adolescents39 was ad- ministered to parents after TAU.

Research Original Investigation Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder

476 JAMA Psychiatry May 2020 Volume 77, Number 5 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

Protocol Changes Changes made to the protocol prior to trial onset are detailed in the protocol in Supplement 1. Most importantly, a no- treatment wait-list control condition was initially added; how- ever, because TAU is a more robust comparator than a wait- list control group,40 it was selected instead. Additionally, during the trial, baseline PARS scores were calculated based on all 7 PARS severity items, instead of 6 of the 7 severity items, as planned at the study onset.22 As a result, 3 children who were randomized actually had 6-item PARS scores less than the intended inclusion criterion cut score of 14 points; following intent-to-treat principles, these children were included in all analyses. Notably, a cut score of 17.5 on the 7-item PARS has been established as optimal in recent psychometric research23; just 2 children in the sample scored at slightly less than this threshold (scores of 17 each).

Statistical Analysis The primary analyses tested treatment effects using general lin- ear mixed models (GLMMs), with study site as a random effect and the baseline score as a covariate. Deviation effect–coding was used in the GLMMs as an initial omnibus test. All covari- ates were centered on the grand mean. Significant deviations from the grand mean were further examined in pairwise con- trasts among the relevant treatment conditions using dummy coding; significant contrasts are described with Cohen d effect size estimates, calculated as the difference of group means at

the end point, using pooled baseline SDs from the full sample as the measure of variability.41 All GLMMs were estimated using HLM 7.0.1 software (Scientific Software International Inc). In- tent-to-treat analyses were conducted by replacing missing val- ues (eg, those attributable to dropout) with multiple imputa- tions using the predictive mean matching method and then testing treatment effects using ordinary least squares regres- sion with the same dummy-coded variables used in the GLMMs. All analyses were by the original assigned groups.

For secondary outcomes, the familywise error rate stem- ming from multiple comparisons was addressed, with the Holm-Bonferroni method applied separately to tests of devia- tion from the grand mean for the BIACA and Coping Cat groups (familywise α = .05). Follow-up contrasts, when performed, were protected with the Fisher least-significant-difference test approach. Because no significant findings were negated by these corrections, unadjusted P values were reported.

Statistical significance was defined as any P value less than .05 (2-tailed). Data analysis for this report occurred from De- cember 2018 to February 2019. All analyses except GLMMs were calculated in SPSS version 24 (IBM).

Results Table 1 presents demographic information for randomized families. Of those enrolled, 167 were randomized (64, 61, and

Table 1. Demographic and Clinical Characteristics for Behavioral Interventions for Anxiety in Children With Autism (BIACA), Coping Cat, and Treatment-as-Usual Groupsa

Characteristics

Participants, No./Total No. (%) BIACA Group

Coping Cat Group

Treatment-as- Usual Group

Female childrenb 21/75 (28) 13/72 (18) 0/19

Latino or Latina childrenc 12/63 (19) 15/54 (28) 3/19 (16)

Child’s racec

African American/African 7/75 (9) 2/71 (3) 3/19 (16)

Asian/Pacific Islander 6/75 (8) 3/71 (4) 1/19 (5)

White 46/75 (61) 48/71 (68) 11/19 (58)

Native American or Alaskan 2/75 (3) 1/71 (1) 0/19

Multiracial

African American and white 0/75 2/71 (3) 1/19 (5)

Asian and white 1/75 (1) 0/71 0/19

Unspecified 1/75 (1) 0/71 0/19

Total household income <$40 000 15/72 (21) 13/71 (18) 5/19 (26)

Father’s education

≤High school diploma 14/72 (19) 12/69 (17) 5/17 (29)

≥4-y College degree 40/72 (56) 40/69 (60) 9/17 (53)

Mother’s education

≤High school diploma 6/74 (8) 5/70 (7) 2/19 (11)

≥4-y College degree 47/74 (64) 50/70 (71) 13/19 (68)

Parents currently married 58/75 (77) 52/71 (73) 12/19 (63)

Autism Diagnostic Observation Schedule–2 algorithm total score, mean (SD)

12.92 (3.88) 13.01 (4.09) 12.39 (4.42)

Childhood Autism Rating Scale total score, mean (SD)

34.63 (4.60) 35.63 (4.94) 33.93 (4.12)

Estimated IQ by Wechsler Intelligence Scale for Children–IV, mean (SD)

102.79 (14.56) 101.64 (15.67) 102.35 (14.54)

a There was a significant treatment group difference for female children (P = .02). No treatment group differences were significant for any of the other demographic variables. The sample sizes vary within groups, because some demographic data were not provided by some families.

b Options for reporting a child’s sex were limited to male and female at the time of the study start. Gender identities were not included from the survey, and future research will correct this omission.

c Race/ethnicity were queried in the same section of the survey, leading many families to report on race or ethnicity but not both, with limited detail. Future research will include more open-ended questions about race/ethnicity in the surveys.

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder Original Investigation Research

jamapsychiatry.com (Reprinted) JAMA Psychiatry May 2020 Volume 77, Number 5 477

© 2019 American Medical Association. All rights reserved.

42 participants at the 3 study sites), 145 completed the study, and 22 discontinued participation (Figure 1). There was no significant difference in discontinuation across the BIACA, Coping Cat, and TAU conditions. A comparison of partici- pants with complete and incomplete data are provided in eTable 1 in Supplement 2; those who discontinued early were more likely to be Latino or Latina (those who discontinued, 8 of 21 participants [38.0%]; those who completed, 22 of 144 par- ticipants [15.3%]; P = .01) and had higher baseline scores on the CAIS-School scale (mean [SD]: those who discontinued, 1.68 [0.75]; those who completed, 1.36 [0.59]; P = .03) and CAIS- Social scale (mean [SD]: those who discontinued, 1.30 [0.70]; those who completed, 0.89 [0.55]; P = .003).

Pretreatment sample characteristics (Table 1) yielded no condition differences or their interaction, with 1 exception: sig- nificant condition differences were found for child sex (fe- male participants: BIACA group, 21 of 75 individuals [28%]; Coping Cat group, 13 of 72 individuals [18%]; TAU group, 0 of 19 individuals [0%]; P = .03), with a greater proportion of boys in TAU relative to other conditions. Sex was included as a co- variate in subsequent analyses. There were several signifi- cant study-site differences on pretreatment characteristics

(eTable 2 in Supplement 2). Participants at study site 1 were more likely to be Latino or Latina (site 1, 20 of 61 participants [33%]; site 2, 10 of 54 participants [16%]; site 3, 0 of 40 par- ticipants; P < .001), Asian/Pacific Islander (site 1, 9 of 61 par- ticipants [15%]; site 2, 1 of 64 participants [2%]; site 3, 0 of 40 participants; P = .005), or multiracial (site 1, 9 of 61 partici- pants [15%]; site 2, 2 of 64 participants [3%]; site 3, 2 of 40 par- ticipants [5%]; P = .04), and less likely to be white (site 1, 40 of 61 participants [66%]; site 2, 54 of 64 participants [84%]; site 3, 34 of 40 participants [85%]; P = .02) or to have an an- nual household income below $40 000 (site 1, 6 of 59 partici- pants [10%]; site 2, 18 of 63 participants [29%]; site 3, 9 of 40 participants [23%]; P = .04). Participants at study site 2 had higher pretreatment Childhood Autism Rating Scale scores than those at study site 1 (mean difference, 1.69 [95% CI, 0.05- 3.33]; P = .04) and study site 3 (mean difference, 4.02 [95% CI, 2.20-5.84]; P < .001), while participants at study site 1 had higher pretreatment Childhood Autism Rating Scale scores than those at study site 3 (mean difference, 2.33 [95% CI, 0.55- 4.11]; P = .01). Participants at study site 2 had higher pretreat- ment ADOS-2 algorithm scores than study site 1 (mean differ- ence, 2.74 [95% CI, 1.40-4.07]; P < .001) and study site 3 (mean

Figure 1. CONSORT Diagram

214 Enrolled 78 Site 1 76 Site 2 60 Site 3

47 Excluded 17 Did not have ASD

6 IQ too low 5 Did not comply 2 Found study too demanding 1 Needed higher level of care

9 Did not have severe anxiety 7 Had no anxiety

167 Randomized

71 Randomized to Coping Cat 26 Site 1 27 Site 2 18 Site 3

19 Randomized to TAU 6 Site 1 7 Site 2 6 Site 3

77 Randomized to BIACA 29 Site 1 30 Site 2 18 Site 3

60 Treatment and follow-up 21 Site 1 23 Site 2 16 Site 3

18 Treatment and follow-up 6 Site 1 6 Site 2 6 Site 3

18 In the primary analytic sample 6 Site 1 6 Site 2 6 Site 3

19 In the analytic sample (intent-to treat) 6 Site 1 7 Site 2 6 Site 3

67 Treatment and follow-up 25 Site 1 29 Site 2 13 Site 3

71 In the analytic sample (intent-to treat) 26 Site 1 27 Site 2 18 Site 3

77 In the analytic sample (intent-to treat) 29 Site 1 30 Site 2 18 Site 3

60 In the primary analytic sample 21 Site 1 23 Site 2 16 Site 3

67 In the primary analytic sample 25 Site 1 29 Site 2 13 Site 3

ASD indicates autism spectrum disorder; BIACA, Behavioral Interventions for Anxiety in Children with Autism; TAU, treatment as usual.

Research Original Investigation Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder

478 JAMA Psychiatry May 2020 Volume 77, Number 5 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

difference [95% CI]: 3.60 [2.10-5.09]; P < .001), while partici- pants at study site 1 and study site 3 did not differ. Study site was treated as a random effect in the GLMMs to incorporate these differences directly in the models.

At pretreatment, 65 of 165 children (27.5%) were using psy- chiatric medication (stimulants, 21 of 165 [12.7%]; selective serotonin reuptake inhibitors, 18 of 165 [10.9%]; α-agonists, 13 of 165 [7.9%]; atypical antipsychotics, 8 of 165 [4.8%]; anticonvulsants, 3 of 165 [1.8%]; monoamine reuptake inhibi- tors, 2 of 165 [1.2%]; and benzodiazepines, 1 of 165 [0.6%]). There were no significant condition or site differences in medi- cation use.

Parents whose children were in the TAU group (17 par- ents) reported their service use at the posttreatment assess- ment. Overall, 12 of the 17 children received psychological or psychiatric care during the TAU period. One child began a new psychiatric medication, and 1 child changed a medication dos- age. Eleven children received a psychological intervention (eg, psychotherapy), whereas 5 of 17 did not receive any ser- vices during TAU.

Therapists inquired about adverse events and completed a structured adverse event form after each CBT session. In terms of serious adverse events,42 1 was reported in the BIACA group (physical abuse by a teacher), and 1 was reported in the Coping Cat group (a child threatened to kill classmates but did not re- port an intention to take action). Both were reported to appro- priate agencies. Neither was deemed to be study associated.

Primary and Secondary Outcomes Table 2 provides descriptive statistics and 95% CIs for pri- mary and secondary outcome measures. The model inter- cepts varied significantly among study sites for PARS scores (SD, 0.27; P < .001), CAIS-School scores (SD, 0.22; P < .001), and CAIS-Social scores (SD, 0.13; P = .01), indicating that mean post- treatment values, irrespective of treatment condition, dif- fered among study sites for these outcomes.

However, random slopes for site were not significant, of- fering no evidence of differential treatment effects at specific sites; these were removed from final models. Table 3 pro- vides GLMM-based estimated differences from the grand mean at the posttreatment assessment for the BIACA and Coping Cat groups, and when those effects were significant, estimated group-mean differences using pairwise comparisons (ie, con- trasts assessed with dummy coding). eTable 3 in Supplement 2 provides effect size estimates for all pairwise comparisons.

For the primary outcome measure (the independent evalu- ator–rated PARS score), there was a significant treatment ef- fect for the BIACA group (difference from the grand mean, −0.352 [95% CI, −0.517 to −0.187]; P < .001) but not for the Coping Cat group (Table 3). Follow-up contrasts indicated that the BIACA group had better results than the Coping Cat group (d, 0.63 [95% CI, 0.27-0.99]; P = .04) and TAU (d, 1.69 [95% CI, 1.10-2.26]; P < .001; Figure 2; Table 3). Exploratory midtreat- ment analyses are presented in the eResults in Supplement 2.

Clinical Global Impression–Improvement Because of separation problems in an initial nonlinear mixed model, the Fisher exact test was used for Clinical Global Im-

pression–Improvement outcomes (response rates are in Table 2). Both the BIACA and Coping Cat groups had higher positive-response rates (61 of 66 participants [92.4%] and 47 of 58 participants [81.0%], respectively) than TAU (2 of 18 par- ticipants [11.1%]; P < .001 for each comparison), but the BIACA and Coping Cat groups did not significantly differ from each other. The absolute risk reduction estimates for no positive treatment response are 81% (95% CI, 58%-90%) for the BIACA group vs the TAU group and 70% (95% CI, 45%-81%) for the Coping Cat group vs the TAU group.

Child Behavior Checklist For the 2 Child Behavior Checklist scales, there was a signifi- cant effect for the BIACA group (Anxious and Depressed scale, −0.134 [95% CI, −0.205 to −0.063]; P < .001; Internalizing scale, −0.074 [95% CI, −0.127 to −0.021]; P = .007) but not the Coping Cat group (Table 3). Follow-up contrasts indicated that the BIACA intervention outperformed the Coping Cat interven- tion on the Child Behavior Checklist Anxious and Depressed scale (d, 0.47 [95% CI, 0.10-0.83]; P = .004) and Internalizing scale (d, 0.50 [95% CI, 0.13-0.86]; P = .01). The BIACA inter- vention also outperformed TAU on these scales (Anxious and Depressed scale: d, 0.68 [95% CI, 0.13-1.22]; P = .002; Internal- izing scale: d, 0.48 [95% CI, −0.07 to 1.01]; P = .04).

Social Responsiveness Scale–2 On the Social Responsiveness Scale–2 DSM-5 Social Commu- nication/Interaction scale, there was a significant effect of the BIACA intervention (Table 3). In follow-up contrasts, the BIACA intervention outperformed the Coping Cat intervention (d, 0.41 [95% CI, 0.04-0.77]; P = .04) and TAU (d, 0.61 [95% CI, 0.05- 1.16]; P = .008). There was no effect of condition on the Social Responsiveness Scale–2 DSM-5 Restricted/Repetitive Behavior scale scores.

CAIS The outcome for the BIACA group differed significantly from the grand mean for the CAIS School and Social subscale scores (Table 3). For the CAIS School subscale, the BIACA interven- tion outperformed TAU (d, 0.75 [95% CI, 0.19-1.29]; P = .003), and the BIACA and Coping Cat interventions did not differ. On the CAIS Social subscale, the outcome for the BIACA group was significantly lower than that of the Coping Cat group (d, 0.28 [95% CI, −0.08 to 0.64]; P = .04) and TAU (d, 0.54 [95% CI, −0.01 to 1.07]; P = .02). There was no effect of condition on the CAIS Family scale scores.

Clinically Significant Improvement Clinically significant improvement was examined in explor- atory analyses by dichotomizing the posttreatment PARS Se- verity score according to whether children exhibited a greater than 35% reduction in values from baseline (ie, clinically sig- nificant anxiety reduction).43 In the BIACA group, 35 of 66 chil- dren (53.0%) achieved this level of symptom relief, in com- parison with 22 of 58 children (37.9%) in the Coping Cat group and 0 of 18 children in TAU (P < .001 by 3-condition likeli- hood ratio test). Both CBT treatments outperformed TAU. In post hoc analyses, children in the BIACA group who had

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder Original Investigation Research

jamapsychiatry.com (Reprinted) JAMA Psychiatry May 2020 Volume 77, Number 5 479

© 2019 American Medical Association. All rights reserved.

achieved clinically significant anxiety reduction by this met- ric exhibited a pattern of consistent and moderate to large dif- ferences on secondary outcome measures in comparison with children in the BIACA group who had not done so; this pat- tern was less distinct in the Coping Cat group (eTable 4 in Supplement 2).

Sensitivity Analyses In the intent-to-treat analyses conducted as described, all sig- nificant contrasts from the GLMMs remained, with 1 excep- tion. The contrast between the participants in the BIACA and TAU groups on the Child Behavior Checklist–Internalizing scale was not significant.

Discussion

The present findings indicate that both versions of a psycho- logical therapy, CBT, are beneficial for children with ASD and maladaptive anxiety. Both CBT conditions had positive ef- fects, but an adapted CBT program (BIACA) outperformed stan- dard-of-practice CBT (Coping Cat) and TAU on the primary out- come measure (independent evaluator–rated PARS scores) and several parent-reports of associated emotion dysregulation symptoms, social-communication symptoms, and adaptive functioning. Both CBT conditions achieved higher rates of posi- tive treatment response on the Clinical Global Impression–

Table 2. Parameters for Primary and Secondary Outcome Measures for the 3 Treatment Groups Before and After Treatment

Scale

Behavioral Interventions for Anxiety in Children with Autism Group Coping Cat Group Treatment-as-Usual Group

Before Treatment After Treatment Before Treatment After Treatment Before Treatment After Treatment

Pediatric Anxiety Rating Scale–Severity

No. of participants 77 66 69 59 19 18

Mean (SD) [95% CI] 3.43 (0.48) [3.32-3.54]

2.13 (0.91) [1.91-2.36]

3.47 (0.47) [3.36-3.59]

2.43 (0.70) [2.25-2.62]

3.28 (0.39) [3.08-3.47]

2.93 (0.59) [2.63-3.22]

Child Behavior Checklist

Anxious and Depressed scale

No. of participants 76 63 69 55 17 17

Mean (SD) [95% CI] 0.83 (0.39) [0.74-0.92]

0.51 (0.29) [0.44-0.59]

0.88 (0.39) [0.79-0.97]

0.69 (0.34) [0.60-0.78]

0.73 (0.28) [0.59-0.87]

0.77 (0.27) [0.63-0.91]

Internalizing scale

No. of participants 76 64 70 55 17 17

Mean (SD) [95% CI] 0.59 (0.28) [0.53-0.66]

0.37 (0.22) [0.32-0.43]

0.64 (0.26) [0.58-0.70]

0.50 (0.26) [0.43-0.57]

0.52 (0.19) [0.42-0.62]

0.50 (0.19) [0.40-0.60]

Social Responsiveness Scale–2

Social Communication/ Interaction scale

No. of participants 74 62 69 54 17 16

Mean (SD) [95% CI] 1.56 (0.33) [1.49-1.64]

1.32 (0.37) [1.23-1.42]

1.59 (0.38) [1.50-1.69]

1.46 (0.40) [1.35-1.57]

1.49 (0.28) [1.34-1.63]

1.53 (0.34) [1.35-1.71]

Restricted/ Repetitive Behavior scale

No. of participants 74 62 69 54 16 16

Mean (SD) [95% CI] 1.39 (0.44) [1.29-1.49]

1.15 (0.45) [1.04-1.27]

1.51 (0.43) [1.41-1.62]

1.30 (0.46) [1.18-1.43]

1.25 (0.47) [1.00-1.50]

1.16 (0.38) [0.96-1.36]

Child Anxiety Impact Scale

School

No. of participants 76 63 69 54 18 17

Mean (SD) [95% CI] 1.38 (0.61) [1.25-1.52]

0.77 (0.57) [0.63-0.92]

1.48 (0.60) [1.34-1.62]

0.88 (0.54) [0.74-1.03]

1.19 (0.70) [0.84-1.54]

1.24 (0.51) [0.97-1.50]

Social

No. of participants 76 64 70 55 17 17

Mean (SD) [95% CI] 0.97 (0.56) [0.85-1.10]

0.49 (0.42) [0.38-0.59]

0.96 (0.62) [0.82-1.11]

0.65 (0.54) [0.51-0.80]

0.70 (0.54) [0.43-0.98]

0.80 (0.50) [0.54-1.05]

Family

No. of participants 75 64 70 55 18 17

Mean (SD) [95% CI] 1.16 (0.63) [1.01-1.31]

0.65 (0.49) [0.53-0.77]

1.12 (0.62) [0.97-1.27]

0.73 (0.51) [0.60-0.87]

0.98 (0.44) [0.76-1.20]

0.88 (0.60) [0.57-1.19]

Clinical Global Impressions–Improvement

Positive treatment response, No./total No. (%)

NA 61/66 (92.4) NA 47/58 (81.0) NA 2/18 (11.1)

Abbreviation: NA, not applicable.

Research Original Investigation Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder

480 JAMA Psychiatry May 2020 Volume 77, Number 5 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

Improvement (each greater than 80%) than TAU (11%). Ac- cordingly, CBT was found to be beneficial for youth with ASD and anxiety, with an adapted CBT approach showing addi- tional advantages.

Consistent with evidentiary standards for assessing treat- ment efficacy,19 this study compared 2 treatments and an ac- tive comparator (TAU), had an adequately powered sample, in- cluded experts in the treatments being investigated, assessed treatment integrity, and used independent evaluators, lend- ing weight to the findings in comparison with preliminary trials.14 The comparison of adapted CBT and standard-of- practice CBT in particular provides a more stringent test of efficacy than previous trials.19 The relative benefit of adapted CBT relative to standard-of-practice CBT was moderate in terms of effect size for the primary outcome measure, with addi- tional advantages in terms of effects on social-communica- tion symptoms and adaptive outcomes. That groups did not differ on PARS scores at midtreatment suggests the need for continued intervention to access full benefits.

The capacity of BIACA to address social-communication symptoms is important, given the synergy between social- communication challenges and anxiety in children with and without ASD.5-8,14,21 Improvements in social-communication functioning did not parallel anxiety reduction to the same de- gree in the Coping Cat intervention. The BIACA intervention

supports social-communication skills through targeted use of evidence-based practices addressing peer engagement, friend- ship, and perspective taking. Improving social functioning may be a pathway to anxiety reduction as well as a goal unto itself; however, anxiety reduction alone may not result in compa- rable improvements in social functioning in children with ASD.

Figure 2. Pediatric Anxiety Rating Scale Scores Before, During and After Treatment in the Treatment-as-Usual (TAU), Coping Cat, and Behavioral Interventions for Anxiety in Children with Autism (BIACA) Groups

4.0

3.0

3.5

2.5

2.0

1.5

1.0

0.5

0

PA R

S M

ea n

Se ve

ri ty

S co

re

Preintervention Midintervention Postintervention

BIACA Coping Cat

TAU

PARS indicates Pediatric Anxiety Rating Scale.

Table 3. Summary Table for General Linear Mixed Models Comparing Treatment Conditions at Posttreatment, Controlling for Baseline Score and Sexa

Measure

Expected Differences From Grand Mean After Treatmentb Contrasts: Expected Group Mean Differences After Treatmentc

BIACA vs Grand Mean Coping Cat vs Grand Mean BIACA vs Coping Cat BIACA vs Treatment as Usual Mean Difference (95% CI) P Value

Mean Difference (95% CI) P Value

Mean Difference (95% CI) P Value

Mean Difference (95% CI) P Value

Pediatric Anxiety Rating Scale

Severity −0.352 (−0.517 to −0.187)

<.001 −0.103 (−0.266 to 0.060)

.22 −0.249 (−0.488 to −0.010)

.04 −0.806 (−1.165 to −0.447)

<.001

Child Behavior Checklist

Anxious and Depressed scale

−0.134 (−0.205 to −0.063)

<.001 0.018 (−0.055 to 0.091)

.63 −0.151 (−0.251 to −0.051)

.004 −0.249 (−0.406 to −0.092)

.002

Internalizing scale −0.074 (−0.127 to −0.021)

.007 0.023 (−0.030 to 0.076)

.41 −0.097 (−0.172 to −0.023)

.01 −0.126 (−0.243 to −0.010)

.04

Social Responsiveness Scale–2

Social Communication/ Interaction scale

−0.117 (−0.195 to −0.039)

.004 −0.002 (−0.076 to 0.080)

.96 −0.115 (−0.223 to −0.007)

.04 −0.235 (−0.406 to −0.065)

.008

Restricted/ Repetitive Behavior scale

−0.049 (−0.147 to 0.049)

.34 0.029 (−0.071 to 0.129)

.57 NA NA NA NA

Child Anxiety Impact Scale

School −0.163 (−0.288 to −0.038)

.01 −0.091 (−0.216 to 0.034)

.16 −0.070 (−0.248 to 0.108)

.44 −0.416 (−0.688 to −0.144)

<.001

Social −0.149 (−0.255 to −0.043)

.006 0.011 (−0.117 to 0.095)

.83 −0.160 (−0.307 to −0.013)

.04 −0.284 (−0.515 to −0.053)

.02

Family −0.095 (−0.205 to 0.015)

.09 −0.018 (−0.128 to 0.092)

.74 NA NA NA NA

Abbreviation: BIACA, Behavioral Interventions for Anxiety in Children with Autism. a Study site was treated as a random effect in all models. The posttreatment

numbers of participants provided in Table 2 reflect sample sizes for each analysis.

b Deviation effect coding was used in general linear mixed models to test treatment effects, with the BIACA and Coping Cat arms compared with the grand mean through the following effect coding for BIACA, Coping Cat, and treatment as usual, respectively: (0, 1, −1) and (1, 0, −1).

c Significant treatment effects for the BIACA or Coping Cat interventions were

followed with contrasts in comparable general linear mixed models using dummy coding to make specific comparisons between conditions (eg, BIACA vs Coping Cat and vs treatment as usual). Estimated group differences for posttreatment mean scores from the models represent the following minueds and subtrahends: BIACA minus the grand mean, Coping Cat minus the grand mean, BIACA minus Coping Cat, BIACA minus treatment as usual. A column for Coping Cat minus treatment as usual contrasts was omitted because none of the primary general linear mixed models using deviation effect coding had significant treatment outcomes for Coping Cat.

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder Original Investigation Research

jamapsychiatry.com (Reprinted) JAMA Psychiatry May 2020 Volume 77, Number 5 481

© 2019 American Medical Association. All rights reserved.

Given the positive effects of the adapted CBT program, what features might contribute to its benefits? The BIACA interven- tion is modular, with components apportioned based on need; some research has identified advantages of modular programs.44

Second, the BIACA program is tailored to children with ASD (eg, it addresses social communication, integrates parents more into treatment sessions, incorporates children’s special inter- ests). Additionally, BIACA treatment sessions were 50% longer than Coping Cat sessions (90 minutes compared with 60 min- utes). The current findings support the benefit of the addi- tional time spent in treatment. For youth with ASD, the added time for parent involvement and an expanded scope of treat- ment targets may contribute the added outcomes.

Limitations Limitations merit consideration. The difference in the dura- tion of treatment sessions and the magnitude of parental in- clusion may be seen as a confound, particularly given the use of parent-reported outcome measures; however, these differ- ences are explicit features of the CBT conditions, and some out- comes were specific, as opposed to universally more favor- able in the BIACA arm. To facilitate generalizations about the treatments, both CBT conditions were implemented accord- ing to their protocols. Furthermore, the specificity of treat- ment effects to ASD populations was not assessed, although these modifications may also benefit children with milder

social-communication difficulties.21 The sample was not as diverse as we would have preferred and was mostly male (consistent with typical ASD sex ratios), including having no female participants in the TAU arm, leading to a sex imbal- ance among conditions (which were controlled for in analy- ses). The TAU condition is also heterogeneous; however, TAU is a relatively stringent comparator.40

Conclusions Cognitive-behavioral therapy appears to be a frontline treat- ment for verbal children with ASD and maladaptive and inter- fering anxiety. Positive response was achieved after manual- based CBT provided by therapists with modest training and weekly supervision. Therapists involved in clinical research with expert supervision may be well prepared to implement CBT for children with ASD; extending these findings to com- munity clinicians without specific ASD expertise is a neces- sary next step. To this end, a training and clinician guidance app has been developed for community clinicians and is avail- able free of charge at https://meya.ucla.edu/. Although super- vision opportunities and expert training are not yet widely ac- cessible, the benefits of CBT appear to justify efforts to disseminate relevant protocols in clinical settings where chil- dren with ASD receive services.

ARTICLE INFORMATION

Accepted for Publication: October 30, 2019.

Published Online: November 22, 2019. doi:10.1001/jamapsychiatry.2019.4160

Author Contributions: Dr Wood had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: J. Wood, Kendall, Lewin, Storch. Acquisition, analysis, or interpretation of data: J. Wood, K. Wood, Kerns, Seltzer, Small, Lewin, Storch. Drafting of the manuscript: J. Wood, Kendall, Kerns, Small, Storch. Critical revision of the manuscript for important intellectual content: J. Wood, K. Wood, Kerns, Seltzer, Lewin, Storch. Statistical analysis: Seltzer, Small. Obtained funding: J. Wood, Kendall, Storch. Administrative, technical, or material support: J. Wood, Lewin, Storch. Supervision: Kendall, K. Wood, Kerns, Lewin, Storch.

Conflict of Interest Disclosures: Dr J. Wood reported grants from National Institute of Child Health and Human Development and National Institute of Mental Health during the conduct of the study. Dr Kendall reported receiving royalties, and his spouse has income from the sales of publications of materials about the treatment of anxiety disorders in youth. Dr Kerns reported receiving honoraria for presenting on her research on anxiety and autism, as well as consultation fees for training staff at other research sites in anxiety and autism assessment, outside the submitted work. Dr Storch reported personal fees from

Levo Therapeutics, Elsevier, Wiley, the American Psychological Association, Springer, and Oxford and grants from Red Cross, ReBuild Texas, the National Institutes of Health, and Texas Higher Education Coordinating Board outside the submitted work. No other disclosures were reported.

Funding/Support: This research was supported by a grant from the National Institute of Child Health and Human Development (R01-HD080098).

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Meeting Presentation: This paper was presented at the Association for Behavioral and Cognitive Therapies convention; November 22, 2019; Atlanta, Georgia.

REFERENCES

1. Baio J, Wiggins L, Christensen DL, et al. Prevalence of autism spectrum disorder among children aged 8 years–Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. MMWR Surveill Summ. 2018;67(6):1- 23. doi:10.15585/mmwr.ss6706a1

2. White SW, Mazefsky CA, Dichter GS, Chiu PH, Richey JA, Ollendick TH. Social-cognitive, physiological, and neural mechanisms underlying emotion regulation impairments: understanding anxiety in autism spectrum disorder. Int J Dev Neurosci. 2014;39:22-36. doi:10.1016/j.ijdevneu.2014. 05.012

3. Kerns CM, Kendall PC, Berry L, et al. Traditional and atypical presentations of anxiety in youth with autism spectrum disorder. J Autism Dev Disord. 2014;44(11):2851-2861. doi:10.1007/s10803-014- 2141-7

4. Kerns CM, Kendall PC. The presentation and classification of anxiety in autism spectrum disorder. Clin Psychol. 2012;19(4):323-347. doi:10. 1111/cpsp.12009

5. Jones AP, Frederickson N. Multi-informant predictors of social inclusion for students with autism spectrum disorders attending mainstream school. J Autism Dev Disord. 2010;40(9):1094-1103. doi:10.1007/s10803-010-0957-3

6. Kaat AJ, Gadow KD, Lecavalier L. Psychiatric symptom impairment in children with autism spectrum disorders. J Abnorm Child Psychol. 2013; 41(6):959-969. doi:10.1007/s10802-013-9739-7

7. Storch EA, Larson MJ, Ehrenreich-May J, et al. Peer victimization in youth with autism spectrum disorders and co-occurring anxiety: relations with psychopathology and loneliness. J Dev Phys Disabil. 2012;24(6):575-590. doi:10.1007/s10882-012- 9290-4

8. Swan AJ, Kendall PC. Fear and missing out: youth anxiety and functional outcomes. Clin Psychol Sci Pract. 2016;23(4):417-435. doi:10.1111/ cpsp.12169

9. Stuart EA, McGinty EE, Kalb L, et al. Increased service use among children with autism spectrum disorder associated with mental health parity law. Health Aff (Millwood). 2017;36(2):337-345. doi:10. 1377/hlthaff.2016.0824

10. Zablotsky B, Pringle BA, Colpe LJ, Kogan MD, Rice C, Blumberg SJ. Service and treatment use among children diagnosed with autism spectrum

Research Original Investigation Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder

482 JAMA Psychiatry May 2020 Volume 77, Number 5 (Reprinted) jamapsychiatry.com

© 2019 American Medical Association. All rights reserved.

disorders. J Dev Behav Pediatr. 2015;36(2):98-105. doi:10.1097/DBP.0000000000000127

11. Reaven J, Blakeley-Smith A, Culhane-Shelburne K, Hepburn S. Group cognitive behavior therapy for children with high-functioning autism spectrum disorders and anxiety: a randomized trial. J Child Psychol Psychiatry. 2012;53(4):410-419. doi:10.1111/ j.1469-7610.2011.02486.x

12. Storch EA, Arnold EB, Lewin AB, et al. The effect of cognitive-behavioral therapy versus treatment as usual for anxiety in children with autism spectrum disorders: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2013;52(2):132-142.e2. doi:10.1016/j.jaac.2012.11.007

13. Storch EA, Lewin AB, Collier AB, et al. A randomized controlled trial of cognitive- behavioral therapy versus treatment as usual for adolescents with autism spectrum disorders and comorbid anxiety. Depress Anxiety. 2015;32(3):174- 181. doi:10.1002/da.22332

14. Wood JJ, Drahota A, Sze K, Har K, Chiu A, Langer DA. Cognitive behavioral therapy for anxiety in children with autism spectrum disorders: a randomized, controlled trial. J Child Psychol Psychiatry. 2009;50(3):224-234. doi:10.1111/j.1469- 7610.2008.01948.x

15. Wood JJ, Ehrenreich-May J, Alessandri M, et al. Cognitive behavioral therapy for early adolescents with autism spectrum disorders and clinical anxiety: a randomized, controlled trial. Behav Ther. 2015;46 (1):7-19. doi:10.1016/j.beth.2014.01.002

16. McNally Keehn RH, Lincoln AJ, Brown MZ, Chavira DA. The Coping Cat program for children with anxiety and autism spectrum disorder: a pilot randomized controlled trial. J Autism Dev Disord. 2013;43(1):57-67. doi:10.1007/s10803-012-1541-9

17. van Steensel FJA, Bögels SM. CBT for anxiety disorders in children with and without autism spectrum disorders. J Consult Clin Psychol. 2015;83 (3):512-523. doi:10.1037/a0039108

18. Hunsche MC, Kerns CM. Update on the effectiveness of psychotherapy for anxiety disorders in children and adolescents with ASD. Bull Menninger Clin. 2019;83(3):326-352. doi:10. 1521/bumc.2019.83.3.326

19. Southam-Gerow MA, Prinstein MJ. Evidence base updates: the evolution of the evaluation of psychological treatments for children and adolescents. J Clin Child Adolesc Psychol. 2014;43 (1):1-6. doi:10.1080/15374416.2013.855128

20. Rao PA, Beidel DC, Murray MJ. Social skills interventions for children with Asperger’s syndrome or high-functioning autism: a review and recommendations. J Autism Dev Disord. 2008;38 (2):353-361. doi:10.1007/s10803-007-0402-4

21. Puleo CM, Kendall PC. Anxiety disorders in typically developing youth: autism spectrum symptoms as a predictor of cognitive-behavioral treatment. J Autism Dev Disord. 2011;41(3):275-286. doi:10.1007/s10803-010-1047-2

22. Kerns CM, Wood JJ, Kendall PC, et al. The treatment of anxiety in autism spectrum

disorder (TAASD) study: rationale, design and methods. J Child Fam Stud. 2016;25(6):1889-1902. doi:10.1007/s10826-016-0372-2

23. Ginsburg GS, Keeton CP, Drazdowski TK, Riddle MA. The utility of clinicians ratings of anxiety using the Pediatric Anxiety Rating Scale (PARS). Child Youth Care Forum. 2011;40(2):93-105. doi:10.1007/ s10566-010-9125-3

24. Kerns CM, Maddox BB, Kendall PC, et al. Brief measures of anxiety in non-treatment-seeking youth with autism spectrum disorder. Autism. 2015; 19(8):969-979. doi:10.1177/1362361314558465

25. Kendall PC, Hedtke KA. Cognitive-Behavioral Therapy for Anxious Children: Therapist Manual. Ardmore, PA: Workbook Publishing; 2006.

26. Kendall PC, Flannery-Schroeder E, Panichelli-Mindel SM, Southam-Gerow M, Henin A, Warman M. Therapy for youths with anxiety disorders: a second randomized clinical trial. J Consult Clin Psychol. 1997;65(3):366-380. doi:10. 1037/0022-006X.65.3.366

27. Kendall PC, Hudson JL, Gosch E, Flannery-Schroeder E, Suveg C. Cognitive- behavioral therapy for anxiety disordered youth: a randomized clinical trial evaluating child and family modalities. J Consult Clin Psychol. 2008;76 (2):282-297. doi:10.1037/0022-006X.76.2.282

28. Swan AJ, Kendall PC, Olino T, et al. Results from the Child/Adolescent Anxiety Multimodal Longitudinal Study (CAMELS): Functional outcomes. J Consult Clin Psychol. 2018;86(9):738- 750. doi:10.1037/ccp0000334

29. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359(26):2753-2766. doi:10.1056/ NEJMoa0804633

30. Fujii C, Renno P, McLeod BD, et al. Intensive cognitive behavioral therapy for anxiety disorders in school-aged children with autism: a preliminary comparison with treatment-as-usual. School Ment Health. 2013;5(1):25-37. doi:10.1007/s12310-012- 9090-0

31. Sze KM, Wood JJ. Enhancing CBT for the treatment of autism spectrum disorders and concurrent anxiety: a case study. Behav Cogn Psychother. 2008;36(4):403-409. doi:10.1017/ S1352465808004384

32. Sze KM, Wood JJ. Cognitive behavioral treatment of comorbid anxiety disorders and social difficulties in children with high-functioning autism: a case report. J Contemp Psychother. 2007;37(3): 133-143. doi:10.1007/s10879-007-9048-y

33. Wood JJ, Klebanoff S, Renno P, Fujii C, Danial J. Individual CBT for anxiety and related symptoms in children with autism spectrum disorders. In: Anxiety in Children and Adolescents with Autism Spectrum Disorder. San Diego, CA: Elsevier Academic Press; 2017:123-141. doi:10.1016/B978-0-12-805122- 1.00007-7

34. Wood JJ, Fujii C, Renno P. Cognitive behavioral therapy in high-functioning autism: review and

recommendations for treatment development. In: Evidence-Based Practices and TREATMENTS For Children With Autism. Boston, MA: Springer; 2011: 197-230. doi:10.1007/978-1-4419-6975-0_7

35. Research Units on Pediatric Psychopharma- cology Anxiety Study Group. The Pediatric Anxiety Rating Scale (PARS): development and psychometric properties. J Am Acad Child Adolesc Psychiatry. 2002;41(9):1061-1069. doi:10.1097/ 00004583-200209000-00006

36. Storch EA, Wood JJ, Ehrenreich-May J, et al. Convergent and discriminant validity and reliability of the pediatric anxiety rating scale in youth with autism spectrum disorders. J Autism Dev Disord. 2012;42(11):2374-2382. doi:10.1007/s10803-012- 1489-9

37. Guy W. ECDEU assessment manual for psychopharmacology. https://archive.org/details/ ecdeuassessmentm1933guyw. Published 1976. Accessed November 6, 2019.

38. Langley AK, Bergman RL, McCracken J, Piacentini JC. Impairment in childhood anxiety disorders: preliminary examination of the child anxiety impact scale-parent version. J Child Adolesc Psychopharmacol. 2004;14(1):105-114. doi:10.1089/ 104454604773840544

39. Horwitz SM, Hoagwood K, Stiffman AR, et al. Reliability of the services assessment for children and adolescents. Psychiatr Serv. 2001;52(8):1088- 1094. doi:10.1176/appi.ps.52.8.1088

40. Weisz JR, Kuppens S, Ng MY, et al. What five decades of research tells us about the effects of youth psychological therapy: A multilevel meta-analysis and implications for science and practice. Am Psychol. 2017;72(2):79-117. doi:10. 1037/a0040360

41. Feingold A. Effect sizes for growth-modeling analysis for controlled clinical trials in the same metric as for classical analysis. Psychol Methods. 2009;14(1):43-53. doi:10.1037/a0014699

42. Rosner R, Rimane E, Frick U, et al. Effect of developmentally adapted cognitive processing therapy for youth with symptoms of posttraumatic stress disorder after childhood sexual and physical abuse: a randomized clinical trial. JAMA Psychiatry. 2019;76(5):484-491. doi:10.1001/jamapsychiatry. 2018.4349

43. Johnco CJ, De Nadai AS, Lewin AB, Ehrenreich-May J, Wood JJ, Storch EA. Defining treatment response and symptom remission for anxiety disorders in pediatric autism spectrum disorders using the Pediatric Anxiety Rating Scale. J Autism Dev Disord. 2015;45(10):3232-3242. doi:10.1007/s10803-015-2483-9

44. Weisz JR, Chorpita BF, Palinkas LA, et al; Research Network on Youth Mental Health. Testing standard and modular designs for psychotherapy treating depression, anxiety, and conduct problems in youth: a randomized effectiveness trial. Arch Gen Psychiatry. 2012;69(3):274-282. doi:10.1001/ archgenpsychiatry.2011.147

Cognitive Behavioral Treatments for Anxiety in Children With Autism Spectrum Disorder Original Investigation Research

jamapsychiatry.com (Reprinted) JAMA Psychiatry May 2020 Volume 77, Number 5 483

© 2019 American Medical Association. All rights reserved.

Copyright of JAMA Psychiatry is the property of American Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.