Biological factors influencing depression in later life: role of aging processes and treatment implications

Abstract

Late-life depression occurring in older adults is common, recurrent, and malignant. It is characterized by affective symptoms, but also cognitive decline, medical comorbidity, and physical disability. This behavioral and cognitive presentation results from altered function of discrete functional brain networks and circuits. A wide range of factors across the lifespan contributes to fragility and vulnerability of those networks to dysfunction. In many cases, these factors occur earlier in life and contribute to adolescent or earlier adulthood depressive episodes, where the onset was related to adverse childhood events, maladaptive personality traits, reproductive events, or other factors. Other individuals exhibit a later-life onset characterized by medical comorbidity, pro-inflammatory processes, cerebrovascular disease, or developing neurodegenerative processes. These later-life processes may not only lead to vulnerability to the affective symptoms, but also contribute to the comorbid cognitive and physical symptoms. Importantly, repeated depressive episodes themselves may accelerate the aging process by shifting allostatic processes to dysfunctional states and increasing allostatic load through the hypothalamic–pituitary–adrenal axis and inflammatory processes. Over time, this may accelerate the path of biological aging, leading to greater brain atrophy, cognitive decline, and the development of physical decline and frailty. It is unclear whether successful treatment of depression and avoidance of recurrent episodes would shift biological aging processes back towards a more normative trajectory. However, current antidepressant treatments exhibit good efficacy for older adults, including pharmacotherapy, neuromodulation, and psychotherapy, with recent work in these areas providing new guidance on optimal treatment approaches. Moreover, there is a host of nonpharmacological treatment approaches being examined that take advantage of resiliency factors and decrease vulnerability to depression. Thus, while late-life depression is a recurrent yet highly heterogeneous disorder, better phenotypic characterization provides opportunities to better utilize a range of nonspecific and targeted interventions that can promote recovery, resilience, and maintenance of remission.

Age‐related subtypes of late life depression and mortality: A prospective clinical cohort study

“…cortisol, kynurenine pathway), psychological, and/or social determinants (e.g health care behaviour) related to depression, 69,70 it is possible that other covariates or pathways not included in this study might explain the mortality risk in this subgroup. Furthermore, although potential interaction between risk and protective factors in LLD are increasingly recognized, 59,70 our sample size was too small to check for potential interactions between the different covariates.…”

“…A possible explanation that physical exercise may improve depressive symptoms as well as cognitive function is that it may target different neurobiological mechanisms that underlie mood and cognitive functioning 58 . However, it is unclear whether successful treatment of depression would shift biological ageing processes back towards a more normative trajectory 59 . Nonetheless, lifestyle changes are difficult and motivation might be low due to a depressed mood as well as cognitive problems.…”

“…Furthermore, although potential interaction between risk and protective factors in LLD are increasingly recognized, 59,70 our sample size was too small to check for potential interactions between the different covariates.…”

“…58 However, it is unclear whether successful treatment of depression would shift biological ageing processes back towards a more normative trajectory. 59 Nonetheless, lifestyle changes are difficult and motivation might be low due to a depressed mood as well as cognitive problems. Furthermore, although the frail depressed group had a higher somatic disease burden, more cardiovascular disease, worse lifestyle and higher inflammation biomarkers compared to non-depressed participants, which all can contribute to accelerated biological ageing and mortality risk, none of these separate pathways explained fully the increased mortality risk in the frail-depressed subgroup.…”

Fluoxetine attenuates stress-induced depression-like behavior due to decrease in pro-inflammatory cytokines in male rats

“…6,7 Although depression affects millions, limited studies have been conducted on the prophylactic approach to its treatment. Several factors precipitate depressive behavior from physical, emotional or environmental (external) stressors such as fatigue, occupational hazards, loss of loved ones or internal stressors, like diseases, inflammation [8][9][10] and alcohol especially in genetically-predisposed individuals. 11 Ethanol increases levels of reactive oxygen species (ROS), which diminish cellular detoxification and repair capacity causing oxidative stress.…”