Aggression and deficient cognitive control problems are widespread in psychiatric disorders,
including major depressive disorder (MDD). These abnormalities are known to contribute
significantly to the accompanying functional impairment and the global burden of disease. Progress
in the development of targeted treatments of excessive aggression and accompanying symptoms
has been limited, and there exists a major unmet need to develop more efficacious treatments for
depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of
precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless,
the aetiology and pathophysiology of MDD has been the subject of extensive research and there
is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we
overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor
signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify
these processes, as many of these pathways are integrated for the neurobiology of MDD. We also
describe the current translational approaches in modelling depression, including the recent advances
in stress models of MDD, and emerging novel therapies, including novel approaches to management
of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.

DOI:https:// doi.org/10.3390/ijms24020915

Journal: International Journal of Molecular Sciences