Major depression as a disorder of serotonin resistance: inference from diabetes mellitus type II

The multifactorial nature of depression resembles that of other complex disorders such as diabetes mellitus or coronary artery disease. However, while for the latter disorders predisposing and risk factors have been identified, such knowledge is still scarce in depression. In this review we propose to use diabetes mellitus, for which characteristic milestones have been condensed to obesity–hyperinsulinaemia–insulin resistance–diabetes mellitus, as a conceptual analogical model. Based on this model we hypothesize that depression develops according to a similar pattern: prolonged psychological stress–hyperserotonism–serotonin resistance–major depression. We review extensive supporting evidence from human studies and animal models of depression, including stress involvement in the aetiology of depression, evidence for increased synaptic serotonin and decreased 5-HT1A receptor activity. Conceptualizing the pathogenesis of depression as a multi-step process may inspire new concepts, which will eventually lead to delineation of additional preventive and therapeutic interventions similar to those currently practised in diabetes.