Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression

Abstract

Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression.

Keywords: Bioenergetics; Bipolar disorder (BD); Brain-derived neurotrophic factor (BDNF); Hypothalamic-pituitary-adrenal axis (HPA axis); Inflammation; Kynurenine; Major depressive disorder (MDD); Mammalian target of rapamycin (mTOR); Metabolism; Proinflammatory cytokine; Stress.