A systematic review of the treatments of anxiety in children with autism spectrum disorder

Study characteristics

Participants in the three pharmacological RCTs ranged in age from 5 to 17 years, with over 90% being male. The diagnosis of ASD was confirmed either by employing Autism Diagnostic Observation Schedule Second Edition (ADOS-2), the Autism Diagnostic Interview-Revised (ADI-R), or both. McDougle, Thom ²¹ included participants with an Intelligence Quotient (IQ) greater than 50, Politte, Scahill ¹⁸ focused on children with IQ above 35, and Simonoff, Mowlem ²² did not specify any IQ cutoff. Two studies examined the use of antidepressants.^21,22 McDougle, Thom ²¹ investigated mirtazapine which was initiated at 7.5 mg/day, with gradual increments to a maximum dose of 45 mg/day. Simonoff, Mowlem ²² examined citalopram, where the starting dose was 2.5 mg/day, with a maximum dose of 20 mg. Politte, Scahill ¹⁸ evaluated the efficacy of extended release guanfacine (GEXR) in children with both ASD and ADHD with a starting dose of 1 mg which was increased to 3 mg/day. Notably, Simonoff, Mowlem ²² was a secondary analysis of the double-blind, placebo-controlled RCT, while Politte, Scahill ¹⁸ and McDougle, Thom ²¹ were randomized, placebo-controlled trials. The studies included moderate sample sizes, ranging from 30 to 149 participants, and featured control groups with blinded evaluators for post-treatment assessments (see Table 3). The duration of treatment was relatively short, with a maximum length of 12 weeks.

Evidence

Among the pharmacological RCTs, all three referred to “anxiety” in general terms without specifying the targeted anxiety disorder. Simonoff, Mowlem ²² reported that 86 out of 149 children (58%) met the threshold for at least one anxiety disorder. To measure response, Simonoff, Mowlem ²² and Politte, Scahill ¹⁸ utilized the Child and Adolescent Symptom Inventory-4 (CASI-4), a 20-item parent-report scale. In contrast, McDougle, Thom ²¹ used the Pediatric Anxiety Rating Scale (PARS), a clinician-rated tool. Although all three studies noted a slight reduction in anxiety symptoms across both groups, these changes were not statistically significant. Simonoff, Mowlem ²² reported that citalopram led to a 16.5% greater reduction in anxiety symptoms compared to placebo, but no group difference was noted. Similarly, the GEXR intervention did not reduce anxiety in the intervention group; however, it did reduce repetitive behaviors and oppositional tendencies. ¹⁸

Adverse events

In Simonoff, Mowlem ²² ’s RCT, 97.3% participants in the citalopram group reported at least one adverse effect compared to 86.8% in the placebo group. Discontinuation occurred in 13 participants from each group. Common side effects associated with citalopram included neuropsychiatric (increased energy, disinhibition, decreased attention, and hyperactivity), insomnia, diarrhea, vomiting, and dry skin. ²² All participants in the mirtazapine group reported experiencing one or more adverse effects like sedation, increased appetite, and irritability. ²¹ One participant discontinued treatment due to irritability and aggression. ²¹ In the GEXR group, four participants discontinued early because of adverse effects, although the specific effects were not detailed. ¹⁸ Six participants among the placebo group discontinued early due to lack of efficacy. ¹⁸

Study characteristics

Psychological treatments include 24 RCTs (see Table 4) with a focus on anxiety symptoms related to GAD, SAD, SA, PD, and SP. To explain how these 24 RCTs relate to each other, they have been further categorized into six subgroups, as depicted in Table 5.

Subgroup 1 in Table 5 includes nine RCTs that utilized standard CBT as an intervention that followed a structured approach to guide therapy involving psychoeducation, cognitive restructuring, behavior interventions, exposure phase, and homework assignments with relapse prevention over 6–16 sessions. Within this subgroup, six studies utilized waitlist (WL) as a control group, where participants did not initiate any new treatment but continued their baseline treatment. They were offered the intervention after the follow-up period. Additionally, three CBT studies within subgroup 1 featured an active control group, a treatment-as-usual (TAU)^32,34,35 where participants continued their preexisting medications or therapy and could make changes to their treatments under supervision. Notably, Frank, Kagan ³⁴ allowed participants in the treatment group to choose between CBT and adapted CBT known as Behavioral Intervention for Anxiety in Children and Adolescents (BIACA) as an intervention.

In subgroup 2 (Table 5), three RCTs^36–38 employed BIACA as an intervention and compared with the TAU group. BIACA features extended therapy sessions lasting 60 to 90 minutes and includes longer exposure phases with specific adaptations consisting of visual supports, simplified language, in-session rewards, and tailored modules addressing special interests.

Subgroup 3 in Table 5 is composed of two RCTs that compared CBT to adapted CBT for ASD. Notably, Guzick, Schneider ¹⁶ is a secondary analysis that also examined moderators and predictors of both standard and adapted CBT. Three more studies incorporated a three-way comparison of CBT vs adapted CBT and TAU classified as subgroup 4. Storch, Wood ¹⁹ utilized a type of CBT called Coping Cat, a program specifically designed for children ages 7 to 13, which emphasizes anxiety management through a structured and child-friendly approach. The other two RCTs in this subgroup utilized standard CBT and compared with adapted CBT and TAU.

Subgroup 5 is composed of three RCTs^41–43 that focused on group-based CBT interventions in school or hospital settings. Kilburn, Sørensen ⁴³ utilized the manualized Cool Kids Anxiety Program for ASD, which features enhanced visual aids, structured worksheets, and relaxation techniques. McConachie, McLaughlin, ⁴¹ and Clarke, Hill ⁴² implemented the “Exploring Feelings” manual, that involves identification of feelings, understanding triggers, and managing anxiety while practicing relaxation tools. All three RCTs in this group included a control group with no active therapy.

Subgroup 6 (Table 5) comprises four studies^6,44–46 that exhibited unique features, therefore, categorized as others. Murphy, Chowdhury ⁶ compared MASSI-CBT (Multimodal Anxiety and Social Skill Intervention) to traditional counseling in a mainstream school setting. MASSI-CBT is specifically designed to provide flexible tailored intervention with focus on coping skill development, whereas counseling sessions focused on issues raised by participants in a supportive manner but with no focus on physical symptoms of anxiety or cognitions. Conaughton, Donovan ⁴⁴ implemented an online CBT program called “Brave,” whereas Storch, Schneider ⁴⁵ developed a novel treatment protocol for Family-Based Exposure Therapy, grounded in BIACA findings. This protocol emphasized family-focused sessions and exposure techniques. Lastly, Rodgers, Goodwin ⁴⁶ introduced the “Coping with Uncertainty in Everyday Situations” (CUES), an 8-week manualized program aimed to enhance children’s ability to manage uncertainty and develop a more flexible mindset. The control group received two parent group sessions on “Understanding Autism,” focusing on psychoeducation.

Among the psychological studies, only 11 specified follow-up periods ranging from one month to one year with Maddox, Miyazaki ³¹ and White, Schry ²⁹ having the longest follow-ups of up to a year. The sample sizes for all studies in this group were decent, ranging from 22 to 280 participants with the majority between 7 and 16 years of age. Cook, Donovan ³⁰ (ages 4 to 6) and Conaughton, Donovan ⁴⁴ (ages 8 to 12) included the youngest participants, while Murphy, Chowdhury ⁶ (ages 12 to 18) and White, Schry ²⁹ (ages 12 to 17) focused on older adolescents. All except three studies relied on clinical interviews alongside the ADOS and/or ADI-R for ASD assessments. Conaughton, Donovan ⁴⁴ and Cook, Donovan ³⁰ used the Childhood Autism Spectrum Disorder (CASD) for high-functioning ASD, while Luxford, Sarah ²⁸ relied on the Social Communication Questionnaire (SCQ). Most participants in the RCTs had an IQ of 70 or higher, except for Wood, Ehrenreich-May, ³⁷ which had a threshold of 85 and ³⁸ which required an IQ above 80. When reported, samples were primarily Caucasian.

Evidence

Among the 24 psychological studies, the PARS and the Anxiety Disorders Interview Schedule for Children and Parents (ADIS-CP) were used as measures of response for all except for White, Schry ²⁹ utilized CASI-4, Luxford, Hadwin, ³³ Conaughton, Donovan, ⁴⁴ and Clarke, Hill ⁴² used Spence Children’s Anxiety Scale, Child and Parent versions (SCAS-C/P), Guzick, Schneider ¹⁶ utilized Clinical Global Impression- severity scale (CGI-S) and Rodgers, Goodwin ⁴⁶ relied on Screen for Child Anxiety and Related Emotional Disorders-parent report (SCARED-P) to assess anxiety symptoms related to GAD, SAD, SA, PD, and SP as their primary outcome measure.

Seventeen RCTs in this group demonstrated that various forms of CBT were effective in reducing anxiety symptoms compared to both WL and TAU. The intervention group showed statistically significant improvements (p < .05) in anxiety symptoms when compared to the control group. However, Murphy, Chowdhury ⁶ reported no significant group difference, with the counseling group showing a notable reduction in social anxiety. Additionally, Rodgers, Goodwin ⁴⁶ indicated minimal differences in anxiety disorder scores between the CUES (coping with uncertainty in everyday situation) and UA (understanding autism) group. When comparing BIACA to CBT, BIACA consistently outperformed both CBT and WL/TAU, with statistically significant reduction in anxiety symptoms as shown in Hollocks, Wood, ³⁹ Guzick, Schneider, ¹⁶ Cho, Wood, ¹⁵ Storch, Wood, ¹⁹ and Wood, Kendall. ⁴⁰ Notably, Guzick, Schneider ¹⁶ reported a rapid reduction in anxiety symptoms during the exposure phase of both CBT and BIACA, compared to the cognitive phase of treatment. The percentage of children who were free of diagnoses varied significantly, ranging from 20% in Conaughton, Donovan ⁴⁴ to 85.7% in Storch, Schneider ⁴⁵ which we were generally maintained at post-treatment follow-ups; however, some return of symptoms was noted, although the levels did not reach pre-treatment levels. Of note, missing sessions and dropouts were common among participants across both groups. Guzick, Schneider ¹⁶ noted that 126 out of 148 participants completed the protocol in full, while Conaughton, Donovan ⁴⁴ found that only 19% attended all 10 sessions and 38% completed the 3-month follow-up.

Study characteristics

Six RCTs were included in this group, comprising 275 participants with the majority of participants being males (see Table 6 for demographics such as age). Gehricke, Lowery ²⁵ had the largest sample size at 148 participants, while Carlisle, Johnson ²³ had the smallest, with only 11 participants. Corbett, Blain, ²⁴ Gehricke, Lowery, ²⁵ and Nguyen, Cardy ²⁷ used ADOS-2 to assess and confirm diagnoses of ASD. In contrast, Hawkins, Weatherby ²⁶ and Carlisle, Johnson ²³ relied on prior clinical diagnosis. Additionally, Maskey, Rodgers ²⁸ employed the SCQ in their assessment of ASD.

Four RCTs in this group included a control or waitlist group (WL). Hawkins, Weatherby ²⁶ assessed the impact of bergamot oil aromatherapy on anxiety symptoms in children attending medical clinics. Carlisle, Johnson ²³ explored the effects of cat adoption on anxiety levels, particularly separation anxiety. Corbett, Blain ²⁴ evaluated a peer-mediated theater-based intervention focused on using peers as models for reciprocal social exchange, while Maskey, Rodgers ²⁸ utilized four virtual reality exposure (VRE) sessions combined with one CBT session targeting SP, excluding injection phobias. The remaining 2 RCTs involved interventions for both groups. Gehricke, Lowery ²⁵ compared an exercise intervention lasting 50 minutes-3 times a week against a sedentary activity, such as playing with Lego or Minecraft, and Nguyen, Cardy ²⁷ described the use of a wearable anxiety meter that monitors heart rate changes and translates them into a visual display, hence, improves awareness of anxiety to initiate relaxation technique. Children in the control group did not receive any feedback of their anxiety level. Overall, follow-up periods ranged from 12 weeks to 6 months, with Maskey, Rodgers ²⁸ including a follow-up at the 6-month mark.

Evidence

The alternate treatment RCTs report mixed results. Two of the six studies specified the anxiety symptoms targeted. Hawkins, Weatherby ²⁶ focused on medical office-induced state anxiety, while Maskey, Rodgers ²⁸ targeted specific phobias. Among the alternative treatments, the State-Trait Anxiety Inventory for Children (STAI-C) was used as the primary outcome measure in three of the six studies.^24,26,27 STAI-C is designed to assess both state anxiety (specific to situations) and trait anxiety (a baseline level of anxiety). Corbett, Blain ²⁴ indicated that the peer-mediated theater-based intervention showed significant differences in anxiety trait but not in state anxiety. Regarding aromatherapy, Hawkins, Weatherby ²⁶ found that exposure to bergamot essential oil could potentially increase anxiety levels rather than decrease them. Nguyen, Cardy ²⁷ found that 15 out of 26 participants felt calmer after using calming techniques facilitated by the wearable anxiety meter. However, no statistically significant difference in anxiety levels was observed between the intervention group and the control group, which did not receive feedback to initiate relaxation techniques. Maskey, Rodgers ²⁸ employed the Spence Children’s Anxiety Scale (SCAS), which is designed for children aged 8 to 15 and reported that the VRE treatment showed an initial positive response in 25% of the participants by reducing anxiety symptoms. This subjective improvement, however, was neither statistically significant nor sustained at follow-up. Carlisle, Johnson ²³ utilized the Screen for Child Anxiety Related Disorders (SCARED), based on parent reports, and found that Cat adoption positively impacted separation anxiety for four children, who maintained their gains at follow-up. Gehricke, Lowery ²⁵ employed SCARED too and observed improvements in anxiety symptoms in all participants; however, the exercise group sustained their gains longer.