The receptor hypothesis and the pathogenesis of depression: Genetic bases and biological correlates

Depression has become one of the most prevalent neuropsychiatric disorders characterized by anhedonia, anxiety, pessimism, or even suicidal thoughts. Receptor theory has been pointed out to explain the pathogenesis of depression, while it is still subject to debate. Additionally, gene abnormality accounts for nearly 40-50% of depression risk, which is a significant factor contributing to the onset of depression. Accordingly, studying on receptors and their gene abnormality are critical parts of the research on internal causes of depression. This review summarizes the pathogenesis of depression from six of the most related receptors and their associated genes, including N-methyl-D-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glucocorticoid receptor, 5-hydroxytryptamine receptor, GABA_A receptor α2, and dopamine receptor; and several "non-classic" receptors, such as metabotropic glutamate receptor, opioid receptor, and insulin receptor. These receptors have received considerable critical attention and are highly implicated in the onset of depression. We begin by providing the biological mechanisms of action of these receptors on the pathogenesis of depression. Then we review the historical and social context about these receptors. Finally, we discuss the limitations of the current state of knowledge and outline insights on future research directions, aiming to provide more novel targets and theoretical basis for the early prevention, accurate diagnosis and prompt treatment of depression.