Citalopram Did Not Significantly Improve Anxiety in Children with Autism Spectrum Disorder Undergoing Treatment for Core Symptoms: Secondary Analysis of a Trial to Reduce Repetitive Behaviors

Abstract

Objective: Anxiety disorders are among the most common co-occurring conditions in autism spectrum disorder (ASD). Despite their prevalence and impact, there are no randomized controlled trials (RCTs) aimed at evaluating the efficacy of selective serotonin reuptake inhibitors (SSRIs) for anxiolysis in this population, who may have a different biological basis for anxiety. Methods: Secondary analyses of the STAART double-blind, placebo-controlled RCT of citalopram in children with ASD examined whether citalopram reduced anxiety measured on the parent-reported Child and Adolescent Symptom Inventory-4 (CASI-4) as the primary outcome. An intention-to-treat analysis involving all 149 participants used multiple imputations for missing data and included baseline stratification factors of age group and site, among others. We prespecified as clinically significant a 33% reduction in anxiety in citalopram versus placebo, coinciding with 80% power. We tested whether communicative ability on the Vineland Communication score moderated treatment effect and explored whether initial anxiety was associated with greater adverse events, which could impact on dose titration and achieving optimal dose. Results: Both groups showed substantial reduction in anxiety. Citalopram was associated with a nonsignificant 16.5% greater reduction (observed coefficient = -0.181, bootstrap standard error = 0.126, p = 0.151, confidence interval = -0.428 to 0.066). Anxiety reports were significantly lower in children with reduced communicative ability, but communicative ability did not moderate the treatment effect (interaction p = 0.294). Initial anxiety levels were not associated with increased adverse effects (interaction ps 0.162-0.954). Conclusion: Citalopram did not statistically significantly improve anxiety in children with ASD. Clinicians should be cautious in their use of SSRIs for this indication. There remains a need for well-powered clinical trials testing the efficacy of SSRIs among autistic children with anxiety disorders.

Keywords: anxiety; autism; autistic disorder; randomized controlled trial; selective serotonin reuptake inhibitors.

FIG. 1.

Primary outcome (anxiety as measured with the CASI-4) for baseline (Screener: placebo n = 70, citalopram n = 67) and endpoint (week 12: placebo n = 58, citalopram n = 56)—missing items imputed for those with 6 or fewer missing of the 20 items. CASI-4, Child and Adolescent Symptom Inventory-4.

FIG. 2.

Estimated effects of citalopram versus placebo on anxiety (as measured with the CASI-4), compared with hypothetical levels of change between baseline and endpoint: Log-transformed scores (left) and back transformed to raw scores (right). The figure provides the actual reduction in placebo and citalopram arms against predictions for no change (same as baseline), a reduction to 67% of baseline (just achieved by placebo—the “placebo effect”) and a further 33% treatment effect, not achieved by citalopram. This proportional effect on the raw score scale is given on the right panel, the size of the expected treatment effect on the raw score increasing with the baseline level of symptoms and no effect expected for those with no symptoms. The red-dotted diagonal line indicates hypothetical continuity of the same level of anxiety. CASI-4, Child and Adolescent Symptom Inventory-4.

FIG. 3.

Venn diagram of anxiety disorders according to the diagnostic algorithm of the CASI-4. CASI-4, Child and Adolescent Symptom Inventory-4.