Fluoxetine vs Cognitive Behavioural Therapy for Childhood Anxiety Disorders

(SMART Trial)

Overseen By Bradley S. Peterson, MD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Hospital Los Angeles

Must not be taking: MAOIs, Antipsychotics, Anticonvulsants, others

Disqualifiers: Neurological disorder, OCD, PTSD, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

316 Participants Needed

Trial Summary

What is the purpose of this trial?

Treatment of every child with anxiety disorder begins with the question of which treatment to start first. Both fluoxetine and CBT have strong empirical support, but few studies have compared their initial effectiveness head-to-head, and none has investigated what to do if the treatment tried first isn't working well-whether to optimize the treatment already begun or to add the other treatment. Aims of the study: 1. The study will assess whether beginning with Cognitive Behavioral Therapy (CBT) or fluoxetine medication is more effective in improving youth-rated anxiety symptoms over the 24-week intervention 2. If the initial intervention fails to induce clinical remission by week 12, the study will assess whether optimizing the initial treatment modality alone, or adding the other modality to the first, yields better symptom improvement by week 24 3. The study will assess whether one sequence of treatment modalities - i.e., CBT followed by optimized CBT; CBT followed by optimized CBT+ medication; medication followed by optimized medication; medication followed by optimized medication + CBT -- is significantly better or worse than predicted from the two main effects 4. The study will assess the stability of treatment response for ≥12 months following completion of the 24-week trial

Do I need to stop my current medications to join the trial?

If you are currently taking fluoxetine, you cannot participate in the trial. If you are on other medications like SSRIs, SNRIs, antidepressants, or benzodiazepines, you may need to taper off these medications to join the study, but this will be done with guidance from your current doctor.

What data supports the effectiveness of the drug fluoxetine for childhood anxiety disorders?

Research shows that fluoxetine can be effective for treating childhood anxiety disorders like separation anxiety and social phobia, with many children showing improvement within 5 weeks of treatment. ^{1 2 3 4 5}

Is fluoxetine safe for children with anxiety disorders?

Fluoxetine, a type of antidepressant, is generally considered safe for children with anxiety disorders, but it requires careful assessment and monitoring due to potential risks like increased suicidal behavior. It is the only SSRI recommended by some health agencies for children, while others advise against using SSRIs in this age group. ^{6 7 8 9 10}

How does fluoxetine differ from other drugs for childhood anxiety disorders?

Fluoxetine is unique because it is a selective serotonin reuptake inhibitor (SSRI) that helps increase serotonin levels in the brain, which can improve mood and reduce anxiety. It is often used in combination with cognitive behavioral therapy (CBT) to enhance treatment effectiveness for childhood anxiety disorders. ^{2 3 4 11 12}

Research Team

Bradley S. Peterson, MD

Principal Investigator

Children's Hospital Los Angeles

Eligibility Criteria

This trial is for children aged 8-17 with moderate to severe anxiety disorders, as measured by specific scales (SCARED-5, SCARED-41, CAIS). They must be fluent in English or Spanish and agree to random treatment assignment. Excluded are those on certain medications like MAOIs or antipsychotics recently, pregnant females not using birth control, anyone with PTSD or unstable medical conditions, and those below a second-grade level in reading/language arts.

Inclusion Criteria

I am between 8 and 17 years old.

I have been diagnosed with an anxiety disorder.

You have high scores on two questionnaires that measure anxiety symptoms, indicating that you may have severe anxiety.

Exclusion Criteria

Patients scoring a 5

Patients with a current/active psychotic diagnosis (schizophrenia, schizoaffective, schizophreniform, psychosis not otherwise specified (NOS), or depression with psychotic features), as determined by medical chart and medical history review by the site director and PI.

I am currently undergoing psychotherapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Cognitive Behavioral Therapy (CBT) or fluoxetine medication over a 24-week intervention period

24 weeks

Optimization

If initial treatment fails by week 12, treatment is optimized or combined with the other modality for better symptom improvement

12 weeks

Follow-up

Participants are monitored for stability of treatment response for at least 12 months following the 24-week trial

≥12 months

Treatment Details

Interventions

• Cognitive Behavioral Therapy (CBT)
• Fluoxetine

Trial Overview The study compares starting treatment with Cognitive Behavioral Therapy (CBT) versus fluoxetine medication for childhood anxiety disorders. If there's no remission by week 12, the study will test if optimizing the initial treatment or adding the other modality improves symptoms more by week 24. It also examines which sequence of treatments is most effective over a year.

Participant Groups

Group I: Medication - Fluoxetine Active Control 1 Intervention

Approved medication by the U.S. Food and Drug Administration (FDA) for treating anxiety disorders in children. The study's starting dose, and minimum permitted, will be 10 mg/day; should that not be tolerated, the patient will be withdrawn from active treatment (but not from study follow-up). After 1 week at 10 mg/day, the dose will increase to 20 mg/day. After completion of week 4, 10 mg/day dose increases will be permitted every other week as tolerated, up to a maximum daily dose of 80 mg/day. If patients are on doses \>20mg/day, the total daily dose can be prescribed either once daily or split into twice daily administrations.

Group II: Cognitive Behavioral Therapy (CBT) Active Control 1 Intervention

Type of talk therapy that aims to identify and replace negative thoughts, using positive behavioral skills to create and maintain positive moods and healthy relationships. The Coping Cat (CC) program will be used as the behavioral intervention for this study.CC is an established evidence-based CBT treatment for pediatric anxiety. It is delivered in individual therapy sessions with anxious children.

Cognitive Behavioral Therapy (CBT) is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Cognitive Behavioral Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Approved in European Union as Cognitive Behavioural Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Approved in Canada as Cognitive Behavioral Therapy for:

• Chronic pain
• Anxiety disorders
• Depressive disorders
• Trauma-related disorders

Who Is Running the Clinical Trial?

Children's Hospital Los Angeles

Lead Sponsor

Trials

257

Recruited

5,075,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

Findings from Research

A systematic review of 21 studies found that fluoxetine use during the first trimester of pregnancy does not significantly increase the risk of major fetal malformations, with an odds ratio of 1.12, indicating safety for the fetus.

However, there is a noted increased risk of cardiac malformations associated with fluoxetine use, with an odds ratio of 1.6 from cohort studies, suggesting that this risk may be influenced by factors such as ascertainment bias in reporting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The fetal safety of fluoxetine: a systematic review and meta-analysis. Riggin, L., Frankel, Z., Moretti, M., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Treatment response in depressed adolescents with and without co-morbid attention-deficit/hyperactivity disorder in the Treatment for Adolescents with Depression Study. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Fluoxetine for the treatment of childhood anxiety disorders: open-label, long-term extension to a controlled trial. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Fluoxetine for the treatment of childhood anxiety disorders. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Open fluoxetine treatment of mixed anxiety disorders in children and adolescents. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

Selective serotonin reuptake inhibitors in pediatric depression: is the balance between benefits and risks favorable? [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Trends in depression and antidepressant prescribing in children and adolescents: a cohort study in The Health Improvement Network (THIN). [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Paroxetine treatment of mood and anxiety disorders in children and adolescents. [2013]

9. Netherlands pubmed.ncbi.nlm.nih.gov

The fetal safety of fluoxetine: a systematic review and meta-analysis. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Selective serotonin reuptake inhibitors in the treatment of paediatric anxiety disorders: a review. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

[Paroxysmal events after anxiety treatment with fluoxetine in a child with autism spectrum disorder]. [2014]

12. England pubmed.ncbi.nlm.nih.gov

Fluoxetine in acute treatment of children and adolescents with obsessive-compulsive disorder: a systematic review and meta-analysis. [2020]