Alterations in Systemic and Cognitive Glucocorticoid Sensitivity in Depression

Abstract

Background: Decades of research point to cortisol insensitivity as a biomarker of depression. Despite a vast literature on cortisol's effects on memory, the role of cortisol insensitivity in core psychological features of depression, such as emotional memory biases, is unknown.

Methods: Sixty-five premenopausal women with varying levels of depression completed this study involving an at-home low-dose dexamethasone suppression test and four experimental sessions (i.e., two visits for memory encoding of emotionally arousing pictures, each of which was followed 48 hours later by a recall test). Participants received 20 mg of oral cortisol (CORT) or placebo prior to encoding. We tested whether systemic cortisol insensitivity measured with the dexamethasone suppression test predicted cognitive sensitivity to CORT, which was operationalized as the change in negatively biased memory formation for pictures encoded following CORT versus placebo administration.

Results: Cortisol insensitivity was associated with more severe depression and flatter diurnal cortisol levels. Cortisol insensitivity predicted negative memory bias for pictures encoded during the placebo session and reduction in negative memory bias for pictures encoded during the CORT (compared with placebo) session, even after accounting for psychiatric symptomatology.

Conclusions: Our findings replicate research showing that cortisol insensitivity predicts depression severity and flatter diurnal cortisol levels. The results further suggest that systemic cortisol insensitivity is related to negative memory bias and its alleviation by cortisol administration. These novel cognitive findings tie together knowledge regarding endocrine and psychological dysfunction in depression and suggest that boosting cortisol signal may cognitively benefit individuals with cortisol insensitivity.

Trial registration: ClinicalTrials.gov NCT03195933.

Keywords: Cortisol; Depression; Diurnal cortisol slope; Glucocorticoid insensitivity; Glucocorticoid resistance; Negative memory bias.

Conflict of interest statement

DISCLOSURES

The authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.. Study Timeline.

Participant eligibility was determined by conducting screening interviews over the phone and in person. Study participation consisted of two memory encoding sessions and two recall test sessions in the lab, in addition to a dexamethasone suppression test (DST) at home. During encoding sessions, which typically occurred 1 week apart, participants completed an emotional memory encoding task approximately 90 minutes after taking a pill containing either 20 mg cortisol (CORT) or placebo. Drug order was randomized across the two sessions and double-blinded. Memory recall for the pictures was tested 48 hours later. All experimental sessions were conducted late in the day when endogenous cortisol levels are relatively low. Participants also completed a DST, which included saliva sampling at home for 4 days (Monday through Thursday). Immediately after collecting the 10pm sample on Day 3, participants took a pill containing a low dose of dexamethasone (0.25 mg). Cortisol response to dexamethasone was measured on Day 4. The majority of DSTs were completed within 10 days of memory testing.

Figure 2.. Associations between Dexamethasone Suppression Test (DST) Feedback Sensitivity and Depression.

DST feedback sensitivity values reflect the difference between pre- and post-dexamethasone morning cortisol levels in μg/dL, with higher values representing greater DST feedback sensitivity (i.e., greater post-dexamethasone cortisol suppression). A) DST feedback sensitivity was inversely correlated with depression severity indexed with the Beck Depression Inventory II (BDI-II), r(64)=−0.27, p=.03, reflecting lower (impaired) DST feedback sensitivity associated with greater depression. B) Depressive disorder diagnosis (“Group”) was related to feedback sensitivity, F(2,62)=3.10, p=.05, reflecting lower (impaired) DST feedback sensitivity in women with current Major Depressive Disorder (MDD) compared to never-depressed controls, F(1,40)=3.96, p=.05. Feedback sensitivity was not significantly impaired for women with mild depressive disorders other than current MDD, F(1,47)=0.18, n.s.

Figure 3.. Dexamethasone Suppression Test (DST) Feedback Sensitivity and Memory Bias.

Scatter plots show how variation in DST feedback sensitivity predicts memory bias. For DST feedback sensitivity, higher values reflect greater feedback sensitivity (i.e., greater post-dexamethasone cortisol suppression). For memory bias in panels A & B, higher values reflect more negatively biased memory formation. A) Lower DST feedback sensitivity was associated with more negatively biased memory for pictures encoded during placebo, r(64)=−0.25, p=.05. B) Feedback sensitivity and memory bias were unrelated for pictures encoded during CORT, r(64)=0.12, n.s. C) Panel C illustrates change in memory bias (CORT minus placebo), with lower numbers representing a greater reduction in negative bias for pictures encoded during CORT compared to placebo (reflected on Y-axis). Lower feedback sensitivity was associated with greater reduction in negative memory bias for pictures encoded during CORT compared to placebo, r(64)=0.32, p=.009. Depression groups are differentiated with symbols in the plots (see legends), which show the wide variability in DST feedback sensitivity within and across groups. The symbols are provided merely for illustration purposes, as DST feedback sensitivity interacted with effects of CORT on memory bias even after controlling for depression severity (see text for detail).