Combining moderators to identify clinical profiles of patients who will, and will not, benefit from aripiprazole augmentation for treatment resistant late-life major depressive disorder

Abstract

Personalizing treatment for late-life depression requires identifying and integrating information from multiple factors that influence treatment efficacy (moderators). We performed exploratory moderator analyses using data from a multi-site, randomized, placebo-controlled, double-blind trial of aripiprazole augmentation. Patients (n=159) aged ≥60 years had major depressive disorder that failed to remit with venlafaxine monotherapy. We examined effect sizes of 39 potential moderators of aripiprazole (vs. placebo) augmentation efficacy using the outcome of percentage reduction in depressive symptom after 12 weeks. We then incorporated information from the individually relevant variables in combined moderators. A larger aripiprazole treatment effect was related to: white race, better physical function, better performance on Trail-Making, attention, immediate, and delayed memory tests, greater psychomotor agitation and suicidality symptoms, and a history of adequate antidepressant pharmacotherapy. A smaller aripiprazole treatment effect was observed in patients with: more pain and more work/activity impairment and libido symptoms. Combining information from race and Trail-Making test performance (base combined moderator (Mb*)) produced a larger effect size (Spearman effect size=0.29 (95% confidence interval (CI): 0.15, 0.42)) than any individual moderator. Adding other individually relevant moderators in the full combined moderator (Mf*) further improved effect size (Spearman effect size=0.39 (95% CI: 0.25, 0.52)) and identified a sub-group benefiting more from placebo plus continuation venlafaxine monotherapy than adjunctive aripiprazole. Combining moderators can help clinicians personalize depression treatment. We found the majority of our patients benefited from adjunctive aripiprazole, but a smaller subgroup that is identifiable using clinical measures appeared to benefit more from continuation venlafaxine plus placebo.

The role of day-to-day emotions, sleep, and social interactions in pediatric anxiety treatment

“…That is, we considered a baseline variable to be a moderator if r m > |.15|, and considered it to be a non-specific predictor if r p > |.15| and it was also not identified as a moderator. This cutoff is similar to cutoffs in previously published applications of the combined moderator method (e.g., see Frank et al, 2015; Smagula et al, 2016; Wallace et al, 2013). We also calculated 95% bootstrap simultaneous confidence intervals (SCIs) based on 10,000 replications for the predictor and moderator effect sizes of the characteristics meeting the minimum ES threshold of |.15|.…”

“…We followed previously published methods (Kraemer, 2013; Smagula et al, 2016; Wallace et al, 2013) to develop an optimal combined moderator of the treatment effect on percent reduction in anxiety. This approach uses multivariable regression to estimate weights for each moderator, with the weights representing the extent to which each moderator distinguishes individual outcome differences between those in CBT versus CCT in context of the other moderators.…”

“…After the weights are estimated, they are extracted and subsequently used to calculate a single optimal combined moderator, M*, for each individual. Similar to Smagula et al (2016), we used LASSO regression (Least Absolute Shrinkage and Selection Optimizer; Tibshirani, 1996) to estimate weights in M*. LASSO regression allows for a large number of potentially correlated individual variables to be included in a model without overfitting.…”

Initial Steps to inform selection of continuation cognitive therapy or fluoxetine for higher risk responders to cognitive therapy for recurrent major depressive disorder

“…The aggregate moderator identified patients with better outcomes in acute-phase psychotherapy versus pharmacotherapy. Similarly, Smagula et al (2016) applied this technique to inform medication augmentation among older adults with MDD.…”

Specific depressive symptoms predict remission to aripiprazole augmentation in late‐life treatment resistant depression

“…Specifically, set shifting moderates remission, anxiety is a poor prognostic factor, and medical burden neither moderates nor predicts remission to aripiprazole augmentation . Other demographic and clinical factors associated with aripiprazole augmentation treatment effects include white race; better physical functioning; better performance on attention, immediate, and delayed memory tests; greater psychomotor agitation and suicidality symptoms; and a history of adequate antidepressant pharmacotherapy …”