Intrinsic reward circuit connectivity profiles underlying symptom and quality of life outcomes following antidepressant medication: a report from the iSPOT-D trial

Abstract

There is a critical need to better understand the neural basis of antidepressant medication (ADM) response with respect to both symptom alleviation and quality of life (QoL) in major depressive disorder (MDD). Reward neurocircuitry has been implicated in QoL, the neural basis of MDD, and the mechanisms of ADM response. Yet, we do not know whether change in reward neurocircuitry as a function of ADM is associated with change in symptoms and QoL. To address this gap in knowledge, we analyzed data from 128 patients with MDD who participated in the iSPOT-D trial and were assessed with functional neuroimaging pre- and post-ADM treatment (randomized to sertraline, venlafaxine-XR, or escitalopram). 58 matched healthy controls were scanned at the same time points. We quantified functional connectivity (FC) of reward neurocircuitry using nucleus accumbens (NAc) seed regions of interest, and then characterized how changes in FC relate to symptom response (primary outcome) and QoL response (secondary outcome). Symptom responders showed an increase in NAc-dorsal anterior cingulate cortex (ACC) FC relative to non-responders (p < 0.001) which was associated with improvement in physical QoL (p < 0.0003), and a decrease in NAc-inferior parietal lobule FC relative to controls (p < 0.001). QoL response was characterized by increases in FC between NAc-ventral ACC for environmental, NAc-thalamus for physical, and NAc-paracingulate gyrus for social domains (p < 0.001). Symptom responders to sertraline were distinguished by a decrease in NAc-insula FC (p < 0.001) and to venlafaxine-XR by an increase in NAc-inferior temporal gyrus FC (p < 0.005). Findings suggest that change in reward neurocircuitry may underlie differential ADM response profiles with respect to symptoms and QoL in depression.

Trial registration: ClinicalTrials.gov NCT00693849.

Figures

Fig. 1. Treatment response as function of symptoms.

a Right and left NAc seed regions of interest (anatomically defined using the WFU PickAtlas). Significant differences in pre-to-post treatment change in FC between symptom responders versus non-responders. b Symptom responders had a significant increase in FC between the right NAc and the right dorsal anterior cingulate cortex (dACC) (peak coordinates 8, −4, 38) compared to symptom non-responders (p < 0.001 voxel-level). There was a significant association between change in HDRS and right NAc-dACC pre-to-post treatment change in FC (R = −0.31, p < 0.001). c Symptom responders also had a significant pre-to-post treatment decrease in FC between the left NAc and the right inferior parietal lobule (peak coordinates 56, −32, 48) compared to CTL (p < 0.001 voxel-level). d Sertraline responders had a significant pre-to-post treatment decrease in FC between the right NAc and the left insular cortex (peak coordinates −32, −36, 4) compared to sertraline non-responders (p < 0.001 voxel-level). e Venlafaxine responders had a significant pre-to-post treatment increase in FC between the right NAc and the right inferior temporal gyrus (peak coordinates 42, −36, −24) compared to venlafaxine non-responders (p < 0.005 voxel-level). Box-and-Whisker plots depict significant pre-to-post treatment between-group differences in FC. Color bars represents t values from the between-group paired t-tests.

Fig. 2. Treatment response as a function of QoL.

Coronal view of the a Right and left NAc seed regions of interest (anatomically defined using the WFU PickAtlas). b Between-group comparison between social QoL responders* and non-responders displayed greater pre-to-post treatment increase in FC between the right NAc seed and the right paracingulate gyrus (peak coordinates +14, +54, −04; this cluster comprises a portion of the frontal medial cortex and ACC) among responders relative to non-responders (WhoSocR > WhoSocNR). c Between-group comparison between physical QoL responders* and non-responders displayed greater pre-to-post treatment increase in FC between the right NAc and the right thalamus (peak coordinates +02, −34, +06) among responders relative to non-responders (WhoPhe-R > WhoPheNR). d Residualized dimensional improvement in environmental QoL (WHO-Env) extracted from patients with MDD showed a significant association with pre-to-post treatment increase in FC between the right NAc and the right ventral anterior cingulate cortex (peak xyz coordinates +04, +46, 00). *QoL responders were defined as exhibiting a 25% or greater improvement in the WHOQOL domain at a voxel-level significant threshold of p < 0.001. Box-and-Whisker plots depict significant pre-to-post treatment between-group FC differences. Color bar represents t values from the between-group paired t-tests.