The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression

Major depressive disorder (MDD) is considered a serious public health issue that adversely impacts an individual’s quality of life and contributes significantly to the global burden of disease. The clinical heterogeneity that exists among patients limits the ability of MDD to be accurately diagnosed and currently, a symptom-based approach is utilized in many cases. Due to the complex nature of this disorder, and lack of precise knowledge regarding the pathophysiology, effective management is challenging. The aetiology and pathophysiology of MDD remain largely unknown given the complex genetic and environmental interactions that are involved. Nonetheless, the aetiology and pathophysiology of MDD have been the subject of extensive research, and there is a vast body of literature that exists. Here we overview the key hypotheses that have been proposed for the neurobiology of MDD and highlight the need for a unified model, as many of these pathways are integrated. Key pathways discussed include neurotransmission, neuroinflammation, clock gene machinery pathways, oxidative stress, role of neurotrophins, stress response pathways, the endocannabinoid and endovanilloid systems, and the endogenous opioid system. We also describe the current management of MDD, and emerging novel therapies, with particular focus on patients with treatment-resistant depression (TRD).