Does Stress Elicit Depression? Evidence From Clinical and Preclinical Studies

Abstract

Exposure to stressful situations may induce or deteriorate an already existing depression. Stress-related depression can be elicited at an adolescent/adult age but evidence also shows that early adverse experiences even at the fetal stage may predispose the offspring for later development of depression. The hypothalamus-pituitary-adrenal axis (HPA-axis) plays a key role in regulating the stress response and dysregulation in the system has been linked to depression both in humans and in animal models. This chapter critically reviews clinical and preclinical findings that may explain how stress can cause depression, including HPA-axis changes and alterations beyond the HPA-axis. As stress does not elicit depression in the majority of the population, this motivated research to focus on understanding the biology underlying resilient versus sensitive subjects. Animal models of depression have contributed to a deeper understanding of these mechanisms. Findings from these models will be presented.

Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs

“…Extensive literature suggesting a link between stress and depression has prompted the so-called ''stress hypothesis of depression'', and substantial efforts have been made to identify drugs that can modulate the HPA-axis for the treatment of MDD [146,147] ( Table 1). One theory has been that stress-induced dysregulation of the HPA-axis leads to depressive episodes via loss of synapses in the PFC and hippocampus and reduction in neuroplasticity [148]. Mifepristone, an antagonist of glucocorticoid receptors that are activated during stress, has been investigated in a comprehensive clinical program for psychotic depression for more than 10 years [149].…”

GABAA receptor-acting neurosteroids: A role in the development and regulation of the stress response

“…It is widely accepted that stress represents a significant risk factor for the development of psychiatric disturbances e.g. depression ( Lupien et al, 2009; Heim et al, 2010; Sickmann et al, 2014 ). Despite the prevalence of major depressive disorders as a leading cause of disability worldwide, the neurobiological processes that underlie the emotional, cognitive and neuroendocrine perturbations associated with these multifactorial disorders remains relatively poorly understood, hindering the development of novel therapeutics.…”

A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression

“…Yet some studies report no change in depression-like behavior after applying chronic stressors. On the other hand, acute stresses are less effective in inducing depression-like behavior in rodents (for more in-depth discussion, see reviews Anisman and Matheson, 2005 ; Sickmann et al, 2014 ). As chronic stress induces imbalance of Arc expression between cortex and amygdala (as discussed in previous section), these rodent behavioral readouts are consistent with the hypothesis that dysregulation of Arc or neuroplasticity is involved in mood disorders.…”