Introduction: Several theories regarding the etiology of Major Depressive Disorder (MDD) provoke challenges in defining the exact pathology of the disorder. Among these theories, the most recurring theories were the monoamine hypothesis, cytokine hypothesis, and endocrine factors. Each of these hypotheses are backed with neurobiological studies and provide unique insight on the etiology of MDD. The current state of the literature of MDD is confusing and complex. There are various theories that explain the pathogenesis of MDD, each supported with evidence from pre-clinical and clinical studies. In this review, we aim to explain the most common theories of MDD and identify connections to the pathological mechanisms of this disease. Methods: A literature search considering inclusion/exclusion criteria was conducted to determine the different theories on the pathology of MDD and their limitations. Results: Using the inclusion/exclusion criteria, 44 articles were analyzed to form the basis of our review. Three main theories were found to be the most recurring, the monoamine hypothesis, cytokine hypothesis, and endocrine factors. Discussion: The monoamine hypothesis suggests that MDD is due to a deficiency of monoamines, specifically the hormone 5-HT, or serotonin. In contrast, the cytokine hypothesis proposes that the abnormal regulation of proinflammatory cytokines is linked to MDD through multiple facets. Finally, dysfunction of the hypothalamic-pituitary-adrenal axis is currently being studied as several papers have reported increased cortisol levels in patients with MDD, suggesting a relation between the two. Conclusion: This paper investigates the recurring theories regarding the pathogenesis of Major Depressive Disorder. However, further analysis revealed that the theories contain several inconsistencies that weaken their respective arguments. This includes unanticipated latency of drug effects, contradictory reports, and failed replications. Many argue that these hypotheses are not the cause of Major Depressive Disorder, but rather a concomitant occurrence. Major Depressive Disorder includes diverse symptoms with various external causes, a matter which makes it difficult to accurately define its pathology. Advanced neurobiological research enables easier diagnosis and the development of effective treatments used by clinicians. Consequently, it is imperative to have a thorough understanding of the pathologic process.
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