A Sequential Multiple Assignment Randomized Trial (SMART) study of medication and CBT sequencing in the treatment of pediatric anxiety disorders

Abstract

Background: Treatment of a child who has an anxiety disorder usually begins with the question of which treatment to start first, medication or psychotherapy. Both have strong empirical support, but few studies have compared their 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.

Methods: This is a single-blind Sequential Multiple Assignment Randomized Trial (SMART) of 24 weeks duration with two levels of randomization, one in each of two 12-week stages. In Stage 1, children will be randomized to fluoxetine or Coping Cat Cognitive Behavioral Therapy (CBT). In Stage 2, remitters will continue maintenance-level therapy with the single-modality treatment received in Stage 1. Non-remitters during the first 12 weeks of treatment will be randomized to either [1] optimization of their Stage 1 treatment, or [2] optimization of Stage 1 treatment and addition of the other intervention. After the 24-week trial, we will follow participants during open, naturalistic treatment to assess the durability of study treatment effects. Patients, 8-17 years of age who are diagnosed with an anxiety disorder, will be recruited and treated within 9 large clinical sites throughout greater Los Angeles. They will be predominantly underserved, ethnic minorities. The primary outcome measure will be the self-report score on the 41-item youth SCARED (Screen for Child Anxiety Related Disorders). An intent-to-treat analysis will compare youth randomized to fluoxetine first versus those randomized to CBT first ("Main Effect 1"). Then, among Stage 1 non-remitters, we will compare non-remitters randomized to optimization of their Stage 1 monotherapy versus non-remitters randomized to combination treatment ("Main Effect 2"). The interaction of these main effects will assess whether one of the 4 treatment sequences (CBT➔CBT; CBT➔med; med➔med; med➔CBT) in non-remitters is significantly better or worse than predicted from main effects alone.

Discussion: Findings from this SMART study will identify treatment sequences that optimize outcomes in ethnically diverse pediatric patients from underserved low- and middle-income households who have anxiety disorders.

Trial registration: This protocol, version 1.0, was registered in ClinicalTrials.gov on February 17, 2021 with Identifier: NCT04760275 .

Conflict of interest statement

Dr. Peterson has received investigator-initiated support from Eli Lilly and Pfizer and has served as a paid consultant to Shire Human Genetic Therapies. He is also President of Evolve Psychiatry Professional Corporation and a paid advisor to Evolve Residential Treatment Centers. Dr. Findling receives or has received research support, acted as a consultant for, and/or has received honoraria from Acadia, Adamas, Aevi, Afecta, Akili, Alkermes, Allergan, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Arbor, Axsome, Daiichi-Sankyo, Emelex, Gedeon Richter, Genentech, Idorsia, Intra-Cellular Therapies, Kempharm, Luminopia, Lundbeck, MedAvante-ProPhase, Merck, MJH Life Sciences,NIH, Neurim, Otsuka, PaxMedica, PCORI, Pfizer, Physicians Postgraduate Press, Q BioMed, Receptor Life Sciences, Roche, Sage, Signant Health, Sunovion, Supernus Pharmaceuticals, Syneos, Syneurx, Takeda, Teva, Tris, and Validus. All other authors declare that they have no competing interests.

Figures

Fig. 1

Postulated Causal Pathways CBT-Specific Factors include exposure and development of coping skills. Common factors include the strength of the therapeutic alliance, clinician relatedness, and rewards associated with treatment. Medication-Specific Factors include direct effects of fluoxetine on brain circuits. Functional Outcomes include improved social relationships, better family and academic functioning, and improved self-esteem, which also function as natural reinforcers, or rewards. Vertical arrows from the Contextualizing Factors represent moderation of the association (shown as an oblique arrow) of a treatment modality with the indicated set of mediators. These contextual factors include Illness Factors such as comorbid illnesses, baseline anxiety severity, and family history of anxiety, as well as Cultural Factors, which include ethnicity and SES

Fig. 2

Schematic of Study Design

Fig. 3

Factorial Structure

Fig. 4

Participant Timeline for Assessments The overall study duration will be 36 months. Trial duration, subsuming stages 1 and 2 each 12 weeks long, is 6 months (24 weeks). Recruitment will occur in months 1–24, and treatment will continue through month 30. Naturalistic follow-up will continue after the 24-week trial to assess the durability of study treatment effects and will range from 6 to 30 months, depending on when participants were recruited into the study. Months 36–43 be devoted to data analysis and draft publication of the manuscript, with submission for publication by month 50

Fig. 5

Schematic for Stage 2 Randomization At the end of Stage 1, participants who meet criteria for remission will continue in maintenance therapy with the same intervention as assigned in Stage 1. Those who do not meet criteria for remission will be randomized to either (1) optimization of the Stage 1 intervention they are already receiving, or (2) optimization of the Stage 1 intervention they are already receiving along with the addition of the other intervention (yielding combined medication + CBT)

Fig. 6

Tests of Mediation. X = Treatment. M = Proposed Mediator. Y = 24-week outcomes. a = coefficient for correlation of X with M (M = aX). b = coefficient for correlation of M with Y (Y = bM). Y = c X = c’ + ab (the total effect of X on Y). M = a X (the effect of X on M). Y = c’ X + b M (direct effect of X on Y). a x b (mediation effect). Algebraic sign of a x b x c (type of mediation – complementary or suppressive)