Orexinergic System Dysregulation in Depression

Depression is an affective disorder characterized, in particular in its more severe form, i.e., major depressive disorder (MDD), by persistent symptoms of unpleasant (dysphoric) mood, inability to experience pleasure (anhedonia), and a generalized loss of interest in most or all normal activities [1]. Depression is often associated with physiological and cognitive symptoms. Physiological symptoms include sleep disorders, changes in appetite, tiredness and lack of energy; cognitive symptoms consist of trouble thinking, concentrating, remembering things, and recurrent thoughts of death and suicidal thoughts. Several brain regions regulating emotion and cognition have been implicated in depression, such as the prefrontal cortex, the cingulate cortex, the nucleus accumbens, the amygdala, the hippocampus and the hypothalamus [2]. A variety of factors seem to be involved in the pathophysiology of depression, such as the occurrence of psychosocial stressful events, changes in the function and effect of monoamines and abnormal functioning of the hypothalamic–pituitary–adrenal (HPA) axis. The activation of the HPA axis is common in depressed patients. The excessive secretion of cortisol damages mature neurons and suppresses normal neurogenesis, leading to a reduction of hippocampal volume. It is important to note that the hippocampus inhibits the hypothalamic corticotrophin releasing factor (CRH) secretion. Thus, the damage to the hippocampus may lead to a vicious cycle in which the loss of inhibitory control of CRH secretion would lead to greater cortisol release, producing additional hippocampal atrophy [3].