Examining raphe-amygdala structural connectivity as a biological predictor of SSRI response

Abstract

Background: Our lab has previously found that structural integrity in tracts from the raphe nucleus (RN) to the amygdala, measured by fractional anisotropy (FA), predicts remission to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD). This could potentially serve as a biomarker for remission that can guide clinical decision-making. To enhance repeatability and reproducibility, we replicated our study in a larger, more representative multi-site sample.

Methods: 64 direction DTI was collected in 144 medication-free patients with MDD from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. We performed probabilistic tractography between the RN and bilateral amygdala and hippocampus and calculated weighted FA in these tracts. Patients were treated with either sertraline or placebo, and their change in Hamilton Depression Rating Scale (HDRS) score reported. Pretreatment weighted FA was compared between remitters and nonremitters, and correlation between FA and percent change in HDRS score was assessed. Exploratory moderator and voxel analyses were also performed.

Results: Contrary to our hypotheses, FA was greater in nonremitters than in remitters in RN-left and right amygdala tracts (p = 0.02 and 0.01, respectively). Pretreatment FA between the raphe and left amygdala correlated with greater, not reduced, HDRS (r = 0.18, p = 0.04). This finding was found to be greater in the placebo group. Moderator and voxel analyses yielded no significant findings.

Conclusions: We found greater FA in nonremitters between the RN and amygdala than in remitters, and a correlation between FA and symptom worsening, particularly with placebo. These findings may help reveal more about the nature of MDD, as well as guide research methods involving placebo response.

Trial registration: ClinicalTrials.gov NCT01407094.

Keywords: Amygdala; Diffusion tensor imaging; Fractional anisotropy; Raphe nucleus; Remission; SSRI.

Conflict of interest statement

Dr. Rajapillai Pillai, Dr. Chuan Huang, Mr. Andrew LaBella, Dr. Mengru Zhang, Dr. Jie Yang, Dr. Melvin McInnis, Dr. Crystal Cooper, Dr. Christine DeLorenzo, and Dr. Ramin Parsey report no relevant or material financial interests that relate to the research described in this paper.

Copyright © 2019. Published by Elsevier B.V.

Figures

Fig. 1.

Coronal (A), Sagittal (B), and axial (C) images of a representative tract (red) from the raphe nucleus (green) to the amygdala (blue). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.

Boxplot of residual fractional anisotropy (FA) after taking age, sex, and site into account. Group means are demarcated by the “X”. Right amygdala is plotted as this is the region with the greatest difference between remitters and non-remitters.

Fig. 3.

Output of linear mixed models relating change in symptom severity to fractional anisotropy (FA) between the raphe nucleus and left amygdala for all participants (A), placebo group only (B), and sertraline group only (C). The placebo group drives the overall correlation. None of other correlations examined were significantly different. HDRS-17: Hamilton Depression Rating Scale, 17 Item.