Combining selective serotonin reuptake inhibitors and cognitive behavioral therapy in youth with depression and anxiety

Abstract

Background: Treatment studies of children and adolescents with internalizing disorders suggest that the combination of a selective serotonin reuptake inhibitor (SSRI) and cognitive behavioral therapy (CBT) consistently produces greater improvement than either treatment alone. We sought to determine how response to combined treatment varies across disorders (anxiety versus depression), and by specific patient characteristics.

Methods: Three large National Institutes of Health-funded trials of children and adolescents with major depression (n = 2) and anxiety disorders (n = 1) were evaluated, each comparing CBT + SSRI to SSRI only, Bayesian Hierarchical Models (BHMs) were used, for endpoint response, time course of response and predictors of response in participants who received SSRI or SSRI+CBT.

Results: SSRI+CBT significantly decreased symptoms by week 4 (p<0.001) across disorders. This improvement continued at week 8 and 12 (p<0.001); however, the additive benefit of CBT over SSRI monotherapy was not statistically significant until week 12 (p<0.001). The fastest response to SSRI+CBT was for patients who were younger, with milder baseline anxiety/depression symptoms and depressive disorders. The slowest response for SSRI+CBT was for boys, adolescents, minoritized children, those with severe symptoms and externalizing disorders.

Limitations: Limitations included inconsistent moderators, variation in the number of observations over time and a lack of genetic or pharmacokinetic variables related to SSRI exposure across studies.

Conclusions: The superiority of SSRI+CBT for youth with depression and anxiety is further supported. For purposes of rapid and greater relief, combination treatment is the superior approach across anxiety and depression and is robust to a range of participant characteristics. However, the added value of CBT (with an SSRI) occurs late in treatment. These findings represent a step towards understanding heterogeneity of treatment response and raise the possibility that interventions could be better tailored or adapted based on patient characteristics.

Keywords: Anxiety; Clinical trial; Depression; Fluoxetine; Major depressive disorder; Paroxetine; SSRI; Sertraline.

Figure 1.. Bayesian Hierarchical Modeling of response, across trials, in patients treated with selective serotonin reuptake inhibitors (SSRIs) or SSRIs+cognitive behavioral therapy (CBT).

N(μ, σ) represents the normal distribution with mean, μ and standard deviation, σ. U(a, b) represents the uniform distribution in the interval a to b. p(δ|data) represents the numerically computed MCMC posterior distributions. CAMS, Child/Adolescent Anxiety Multimodal Study; TORDIA, Treatment of SSRI-Resistant Depression Study; TADS, Treatment of Adolescent Depression Study

Figure 2:. Improvement in youth with depressive and anxiety disorders who received treatment with SSRIs or SSRIs+CBT.

Individual trajectories of improvement are shown for patients who receive SSRIs (blue line) or SSRI+CBT (red line) in panel A. Endpoint improvement for patients who received SSRI monotherapy or SSRI+CBT are shown in B and C. Note: Positive values reflect less improvement. For example, in 2B, a large and significant value corresponds with patients who had greater severity improving significantly less, matching the trajectories for symptom severity comparisons shown in Figure 3F

Figure 3:. Improvement Trajectories in Youth Treated with Selective Serotonin Reuptake Inhibitors (SSRIs) or SSRI+cognitive behavioral therapy (CBT).

P-values are shown for significant differences in trajectory. Differences in endpoint response are shown in Figure 2. MDD, major depressive disorder; sx, symptoms.

Figure 4:

Heterogeneity in Improvement Trajectory among Patients Treated with Selective Serotonin Reuptake Inhibitors (SSRIs) (A) or SSRI+Cognitive Behavioral Therapy (CBT) (B).