Amygdala Reactivity to Emotional Faces in the Prediction of General and Medication-Specific Responses to Antidepressant Treatment in the Randomized iSPOT-D Trial

Abstract

Although the cost of poor treatment outcomes of depression is staggering, we do not yet have clinically useful methods for selecting the most effective antidepressant for each depressed person. Emotional brain activation is altered in major depressive disorder (MDD) and implicated in treatment response. Identifying which aspects of emotional brain activation are predictive of general and specific responses to antidepressants may help clinicians and patients when making treatment decisions. We examined whether amygdala activation probed by emotion stimuli is a general or differential predictor of response to three commonly prescribed antidepressants, using functional magnetic resonance imaging (fMRI). A test-retest design was used to assess patients with MDD in an academic setting as part of the International Study to Predict Optimized Treatment in Depression. A total of 80 MDD outpatients were scanned prior to treatment and 8 weeks after randomization to the selective serotonin reuptake inhibitors escitalopram and sertraline and the serotonin-norepinephrine reuptake inhibitor, venlafaxine-extended release (XR). A total of 34 matched controls were scanned at the same timepoints. We quantified the blood oxygen level-dependent signal of the amygdala during subliminal and supraliminal viewing of facial expressions of emotion. Response to treatment was defined by ⩾ 50% symptom improvement on the 17-item Hamilton Depression Rating Scale. Pre-treatment amygdala hypo-reactivity to subliminal happy and threat was a general predictor of treatment response, regardless of medication type (Cohen's d effect size 0.63 to 0.77; classification accuracy, 75%). Responders showed hypo-reactivity compared to controls at baseline, and an increase toward 'normalization' post-treatment. Pre-treatment amygdala reactivity to subliminal sadness was a differential moderator of non-response to venlafaxine-XR (Cohen's d effect size 1.5; classification accuracy, 81%). Non-responders to venlafaxine-XR showed pre-treatment hyperreactivity, which progressed to hypo-reactivity rather than normalization post-treatment, and hypo-reactivity post-treatment was abnormal compared to controls. Impaired amygdala activation has not previously been highlighted in the general vs differential prediction of antidepressant outcomes. Amygdala hypo-reactivity to emotions signaling reward and threat predicts the general capacity to respond to antidepressants. Amygdala hyper-reactivity to sad emotion is involved in a specific non-response to a serotonin-norepinephrine reuptake inhibitor. The findings suggest amygdala probes may help inform the personal selection of antidepressant treatments.

The pulvinar nucleus and antidepressant treatment: dynamic modeling of antidepressant response and remission with ultra-high field functional MRI

“…While all applied antidepressants were demonstrated to be superior to placebo [59,60], this does not rule out unwanted placebo effects in this study. Placebo control in fMRI treatment trials is currently infrequently applied [8,61,62]. For translation of pharmacological fMRI findings to clinic placebo-controlled validation might be necessary.…”

On antidepressants and still feeling low

“…To serve as a basis of comparison for more complex models, a regression model consisting solely of clinical and demographic variables was used to classify functional remission (Table S3). In the first step, age, years of education, baseline depression severity, and MDD episode duration were included as predictors based on their previous associations with treatment success (30,32). This model overall showed a trend toward significance (χ 2 = 73.07, df = 4, P = 0.067) (Table S3).…”

“…Specifically, preintervention amygdala hypoengagement in response to subliminal fearful and angry faces (a signal of potential threat) and happy faces (a signal of social reward) have separately been associated with better antidepressant response. Moreover, amygdala reactivity in responders to both negatively and positively valenced stimuli increased toward normalization following antidepressant intervention (30). Increasing levels of ELS have also been associated with poorer outcomes to pharmacotherapy, pharmacotherapy combined with psychotherapy, and psychotherapy alone (4,5,14).…”

“…Evidence from rodents and humans has implicated the amygdala as a target of antidepressants (12,13). Congruent with this framework, amygdala engagement in response to both positively and negatively valenced stimuli distinguished antidepressant responders and nonresponders (30). Specifically, preintervention amygdala hypoengagement in response to subliminal fearful and angry faces (a signal of potential threat) and happy faces (a signal of social reward) have separately been associated with better antidepressant response.…”

From Pharmacogenetics to Imaging Pharmacogenetics: Elucidating Mechanisms of Antidepressant Response

“…MRI studies have identified several potential imaging markers for antidepressant response. For example, normalization of amygdala hypoactivity during the face-processing task in responders, but not in nonresponders [13] has been reported. Activation during the go/no-go task in the inferior frontal gyrus, the amygdala, insula and the anterior cingulate cortex at baseline of antidepressant treatment has been correlated with reduction of depression symptoms during the course of treatment [14].…”