Systemic Inflammation at the Crossroad of Major Depressive Disorder and Comorbidities: A Narrative Review.

Major Depressive Disorder (MDD) represents a global challenge due to its high prevalence worldwide. Inflammation is the most extensively studied and plausible biological pathway involved in the onset of MDD. Individuals with MDD often exhibit low-grade inflammation, characterized by immune system dysregulation and activation of pro-inflammatory pathways. Elevated inflammation is also associated with a reduced response to antidepressant therapies, suggesting that targeting inflammation could represent a promising therapeutic approach for MDD. MDD frequently co-occurs with other pathological conditions, including cardiometabolic, autoimmune, and chronic pain disorders. These comorbidities further complicate MDD treatment and contribute to reduced antidepressant efficacy. Like MDD, these disorders are characterized by a strong inflammatory component, and several cytokines and pro-inflammatory mechanisms altered in MDD are also found in these comorbid conditions. This narrative review explores inflammation as a shared biological mechanism in MDD and its most frequent comorbidities, to provide a comprehensive understanding of the interplay between inflammation and these comorbid conditions. Persistent low-grade inflammation may help explain the high rate of bidirectional co-occurrence between MDD and its comorbidities. Moreover, it may represent a target for better understanding the molecular mechanisms driving this co-occurrence, potentially contributing to the development of tailored treatment and improving antidepressants response rates.