Yohimbine-Induced Reactivity of Heart Rate Variability in Unmedicated Depressed Patients With and Without Adverse Childhood Experience.

Christian Eric Deuter,Linn Kristina Kuehl,Katja Wingenfeld,Christian Otte

doi:10.3389/fpsyt.2021.734904

Abstract

Stressful life events play a role in the pathogenesis of major depressive disorder (MDD) and many patients with MDD were exposed to developmental stress due to adverse childhood experiences (ACE). Furthermore, dysregulation of the autonomic nervous system and higher incidence of cardiovascular disease are found in MDD. In MDD, and independently in individuals with ACE, abnormalities in heart rate variability (HRV) have been reported. While these are often confounded, we systematically investigated them with a study which included MDD patients with/without ACE as well as healthy individuals with/without ACE. With this study, we investigated the influence of noradrenergic stimulation on HRV reactivity in unmedicated participants in a randomized, double-blind, repeated measures design. Our sample consisted of men and women with MDD and ACE (n = 25), MDD without ACE (n = 24), healthy participants with ACE (n = 27), and without ACE (n = 48). Participants received a 10 mg single dose of the alpha-2 antagonist yohimbine that increases noradrenergic activity or placebo on 2 separate days, with ECG recordings before and after drug administration at defined intervals. We found lower basal HRV in MDD and ACE: patients with MDD had reduced RMSSD whereas participants with ACE had lower LF-HRV. Contrary to our hypothesis, there was no effect of yohimbine. With this study, we were able to replicate previous findings on HRV differences in MDD and ACE. From the null effect of yohimbine, we conclude that the yohimbine-induced sympathetic activation is not a significant driver of HRV in MDD and ACE.

Highlights

Major Depressive Disorder (MDD) is associated with a dysregulation of the autonomic nervous system (ANS), reflected in a disturbed balance between the sympathetic and parasympathetic branch of the ANS [1,2,3]
Since a complex interplay between the sympathetic and parasympathetic nervous systems can be assumed, we report those well-established parameters that are primarily associated with the parasympathetic nervous system, i.e., the root mean square of successive differences (RMSSD) in the time domain and the high frequency (HF)-heart rate variability (HRV) for the frequency domain
We found an increase in HRV over the factor “time” [RMSSD: F(2,224) = 15.61, p < 0.001, η2p = 0.12, HF: F(2,224) = 8.59, p < 0.001, η2p = 0.07, low frequency (LF): F(2,224) = 24.58, p < 0.001, η2p = 0.18]; this effect was moderated by the betweensubjects factor “time × MDD” [RMSSD: F(2,224) = 8.46, p < 0.001, η2p = 0.07, HF: F(2,224) = 5.67, p < 0.01, η2p = 0.05, LF: F(2,224) = 4.27, p = 0.02, η2p = 0.04]

Summary

Introduction

Major Depressive Disorder (MDD) is associated with a dysregulation of the autonomic nervous system (ANS), reflected in a disturbed balance between the sympathetic and parasympathetic branch of the ANS [1,2,3]. HRV in MDD and ACE lower heart rate variability (HRV) when compared to healthy controls, both under resting condition and measured as reactivity after stress [5, 6]. Lower variability of the heart rate can be interpreted as an reduced adaptability of the organism, i.e., lower capacity to adjust to current demands [7]. While it is established that high frequency changes in heart rate are mediated by the vagus nerve and the parasympathetic nervous system, the hypo-reactivity found in MDD patients could as well be attributed to constant sympathetic dysregulation [8,9,10]

Objectives

Methods

Results

Conclusion