Fluoxetine, CBT, and Combination(s) Show Similar Benefit in Youth Anxiety

A randomized clinical trial published in The American Journal of Psychiatry found that fluoxetine, cognitive-behavioral therapy (CBT), their combination, and different sequencing approaches produced similar symptom reductions in youths with anxiety disorders over 24 weeks.

The study evaluated treatment sequencing in pediatric anxiety disorders, including whether care should begin with fluoxetine or exposure-based CBT. For participants whose symptoms did not remit after 12 weeks, the trial also assessed whether outcomes were better with optimization of the initial treatment or with the addition of the other treatment modality.

The 24-week, single-blind sequential multiple assignment randomized trial (SMART) included 316 youths ages 8 to 17 years with severe anxiety, high levels of sociodemographic disadvantage, and common co-occurring diagnoses. Participants were treated in primary care and mental health clinics. They were initially randomized to fluoxetine or weekly “Coping Cat” CBT, and nonremitters after 12 weeks were randomized again to optimized monotherapy or combination therapy.

The primary outcome was change in youth-reported Screen for Child Anxiety Related Emotional Disorders (SCARED) score. Across the full trial, youth-reported SCARED scores declined 31.7%. Improvement did not differ significantly by initial treatment, although CBT showed a nonsignificant advantage over medication at 24 weeks. Among week-12 nonremitters, combination therapy did not produce significantly greater week-24 improvement than continuing monotherapy.

The authors reported that initial CBT followed by combination therapy separated from other sequences on a subset of measures. Subgroup findings suggested non-Hispanic White youths benefited more from initiating fluoxetine and continuing it after week 12, while racial and ethnic minority youths benefited more from transitioning to combination therapy after week 12. The authors concluded that patients, families, and clinicians have a range of treatment options and may optimize outcomes based on stakeholder preference.

Sources: Peterson BS, West AE, Weersing VR, et al. A pragmatic SMART study of medication and CBT sequencing in pediatric anxiety disorders: a randomized clinical trial. Am J Psychiatry. 2026;XX:1-14. doi:10.1176/appi.ajp.20251037