Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integration of the wide array of biological underpinnings of MDD, including gut dysbiosis and permeability, as well as developmental and social stressors, which can act to suppress the capacity of mitochondria to upregulate the melatonergic pathway, with consequences for oxidant-induced changes in patterned microRNAs and subsequent patterned gene responses. This is placed within a development context, including how social processes, such as discrimination, can physiologically regulate a susceptibility to MDD. Future research directions and treatment implications are derived from this.
Keywords: amygdala; aryl hydrocarbon receptor; astrocytes; depression; gut microbiome; melatonin; mitochondria; racism; stress; treatment.