Current concepts of pathogenesis of depressive disorder: A literature review

Abstract

Introduction: Despite the high prevalence of depressive disorders, the pathogenesis of depression has not been fully established. Recently, a significant number of works have been published demonstrating mechanisms of development of this pathology that differ from classic monoaminergic theory. In-depth study of such mechanisms can be used as new approaches to the design of more advanced antidepressant drugs.

Materials and Methods: A search of literary sources was conducted in Google Scholar, PubMed and Cochrane databases using keywords in English: “pathogenesis of depression”, “major depressive disorder”, “β-arrestin”, “glutamate depression”, “GABA and depression”, and “neuroinflammation”. The exclusion criteria were sources published earlier than 2015. At the first step, 127 sources were chosen, but after excluding papers containing duplicated or not up-to-date information, only 40 articles were included in the review. The obtained data were briefly summarized in the form of a review article.

Results and Discussion: Translational MRI data indicate that hippocampal volume loss in depression is likely due to a disruption in serotonin-dependent neuroplasticity, which is reversible with SSRI treatment. It is believed that the therapeutic effect of these drugs is not due to a direct effect on symptoms, but rather to a restructuring of neuronal energy metabolism due to increased serotonin levels, which initiates restorative processes in the brain. β-arrestin pathway is alternative to classic in G-proteins, and some data suggest that β-arrestin-2 expression is exactly the key component of fluoxetine’s mechanism of action. Current research reveals structural, functional, and neurochemical abnormalities in GABA- and glutamate-dependent neurons that can lead to impaired signaling in the cerebral cortex and hippocampus. According to current concepts, the molecular mechanisms of these changes are associated with stress-induced excitotoxic effects, occurring against a background of elevated levels of adrenal glucocorticoids and inflammatory cytokines. Current data confirm the key role of neuroinflammation in the development of depression. Animal models of depression consistently show elevated levels of proinflammatory cytokines (IL-1β, IL-6, TNF-α). Multiple psychosocial stressors have been shown to accelerate the development of neuroinflammation, which, in turn, contributes to the progression of major depressive disorder.

Conclusion: Despite a significant amount of research in this area, the role of additional factors in the pathogenesis of depression continues to be actively explored. Established pathogenetic models do not fully explain the disorder’s clinical heterogeneity, and current research focuses on clarifying the contribution of less studied elements, including immune dysfunction, oxidative stress, and the complex interactions between various neurotransmitter systems that go beyond the classical monoamine hypothesis.

Graphical Abstract