Early Life Stress Exposure and Amygdala Reactivity Predict Symptom Improvement on Antidepressants

Post by Elisa Guma

What's the science?

Amygdala reactivity and exposure to early life stress have been implicated in the neurobiology of depression. However, not all individuals who experience early life stress develop depression, suggesting that there may be an interaction between the stressor and its effect on emotional brain circuitry (which includes the amygdala). Antidepressant treatment, shown to alter amygdala structure and function, is the standard for depression treatment, however, it only works for a subset of individuals; research suggests that those with high levels of early life stress have weaker outcomes. This week in PNAS, Goldstein-Piekarski and colleagues investigated whether a history of early life stress and amygdala reactivity to emotional faces may be predictive of antidepressant response in humans with depression. 

How did they do it?

Participants were enrolled in the International Study to Predict Optimized Treatment in Depression, with a confirmed diagnosis of nonpsychotic major depressive disorder. Participants were divided into three groups based on their exposure to early life stress, low (≤1 event), mid- (2–5 events), and high- (≥6 events), and evaluated using a 19-item Early Life Stress Questionnaire. Functional remission was defined as a return of symptoms to a healthy range and calculated based on a combined measure of clinician-rated depression symptom severity, self-reported symptom severity, and observer-rated functional capacity. Amygdala reactivity was measured using functional magnetic resonance imaging, while participants were shown images of happy and fearful faces as well as neutral comparison faces (drawn from a standardized series of facial expressions).

The authors used hierarchical logistic regression models to predict functional remission and used receiver operating characteristic curves to plot the performance of their regression models (this plots true and false positives). Leave-one-out cross validation was used to derive an unbiased threshold to classify remitters and non-remitters, improving the generalizability of their model. A series of successive regression models were used, starting with a simple covariate model as a baseline that included clinical and demographic variables (age, educational level, duration of MDD episode, social/occupational function, depression symptoms). Next, the authors tested the addition of early life stress level (i.e., low, mid, high) and amygdala reactivity to happy faces, followed by early life stress level and amygdala reactivity to fearful faces, and finally, an additive model with both interactions.

What did they find?

First, the authors confirmed that patient groups that achieved functional remission did not differ from those that did not achieve remission in terms of the demographic variables. Next, they found that their baseline model that included only demographic and clinical information showed a trend towards significance in its ability to classify remission. Including the interaction between early life stress and amygdala reactivity to happy faces or fearful faces as predictors in the model significantly improved the accuracy of prediction, however, both of these models had a higher probability of false positives or negatives. Finally, the additive model which included both the interaction term between early life stress and amygdala reactivity to happy faces as well as early life stress and amygdala reactivity to fearful faces further increased the ability to predict functional remission, suggesting good generalizability of this model.

What's the impact?

The findings presented here suggest that functional remission due to antidepressant treatment may depend on an individual’s history of early life stress and the responsiveness of their amygdala to facial emotion. Further, the authors present a model which predicts, with a high degree of accuracy, those individuals who respond well to antidepressant treatment. This may be of clinical utility as a tool for screening individuals prior to initiating treatments. Finally, the results advance our understanding of how early life stress and amygdala reactivity function synergistically to predict subsequent remission from depression.  

Goldstein-Piekarski, et al. Human amygdala engagement moderated by early life stress exposure is a biobehavioral target for predicting recovery on antidepressants. PNAS (2016). The original scientific publication here.