Worldwide, the incidence of major depressive disorder (MDD) is increasing annually, resulting in greater economic and social burdens. Moreover, the pathological mechanisms of MDD and the mechanisms underlying the effects of pharmacological treatments for MDD are complex and unclear, and additional diagnostic and therapeutic strategies for MDD still are needed. The currently widely accepted theories of MDD pathogenesis include the neurotransmitter and receptor hypothesis, hypothalamic-pituitary-adrenal (HPA) axis hypothesis, cytokine hypothesis, neuroplasticity hypothesis and systemic influence hypothesis, but these hypothesis cannot completely explain the pathological mechanism of MDD. Even it is still hard to adopt only one hypothesis to completely reveal the pathogenesis of MDD, thus in recent years, great progress has been made in elucidating the roles of multiple organ interactions in the pathogenesis MDD and identifying novel therapeutic approaches and multitarget modulatory strategies, further revealing the disease features of MDD. Furthermore, some newly discovered potential pharmacological targets and newly studied antidepressants have attracted widespread attention, some reagents have even been approved for clinical treatment and some novel therapeutic methods such as phototherapy and acupuncture have been discovered to have effective improvement for the depressive symptoms. In this work, we comprehensively summarize the latest research on the pathogenesis and diagnosis of MDD, preventive approaches and therapeutic medicines, as well as the related clinical trials.

It is well known that sleep disorders are harmful to people's health and performance, and growing evidence suggests that sleep deprivation (SD) can trigger neuroinflammation in the brain. The nucleotide‐binding domain and leucine‐rich repeat protein‐3 (NLRP3) inflammasome is reported to be relevant to the neuroinflammation induced by SD, but the regulatory signaling that governs the NLRP3 inflammasome in SD is still unknown. Meanwhile, whether the regulatory action of antidepressants in astrocytes could affect the neuroinflammation induced by SD also remains obscure. In this study, we were the first to discover that the antidepressant fluoxetine, a type of specific serotonin reuptake inhibitor widely used in clinical practice, could suppress the neuroinflammation and neuronal apoptosis induced by SD. The main findings from this study are as follows: (i) SD stimulated the expression of activated NLRP3 inflammasomes and the maturation of IL‐1β/18 via suppressing the phosphorylation of STAT3 in astrocytes; (ii) SD decreased the activation of AKT and stimulated the phosphorylation of GSK‐3β, which inhibited the phosphorylation of STAT3; (iii) the NLRP3 inflammasome expression stimulated by SD was partly mediated by the P2X7 receptor; (iv) an agonist of STAT3 could significantly abolish the expression of NLRP3 inflammasomes induced by an agonist of the P2X7 receptor in primary cultured astrocytes; (v) the administration of fluoxetine could reverse the stimulation of NLRP3 inflammasome expression and function by SD through elevating the activation of STAT3. In conclusion, our present research suggests the promising possibility that fluoxetine could ameliorate the neuronal impairment induced by SD. image

Ketamine, a general anaesthetic and psychotomimetic drug, exerts rapid, potent and long-lasting antidepressant effect, albeit the cellular and molecular mechanisms of this action are yet to be discovered. Besides targeting neuronal NMDARs fundamental for synaptic transmission, ketamine affects the function of astroglia the key homeostatic cells of the central nervous system that contribute to pathophysiology of psychiatric diseases including depression. Here we review studies revealing that (sub)anaesthetic doses of ketamine elevate intracellular cAMP concentration ([cAMP]i) in astrocytes, attenuate stimulus-evoked astrocyte calcium signalling, which regulates exocytotic secretion of gliosignalling molecules, and stabilize the vesicle fusion pore in a narrow configuration possibly hindering cargo discharge or vesicle recycling. Next we discuss how ketamine affects astroglial capacity to control extracellular K+ by reducing cytoplasmic mobility of vesicles delivering the inward rectifying potassium channel (Kir4.1) to the plasmalemma. Modified astroglial K+ buffering impacts upon neuronal excitability as demonstrated in the lateral habenula rat model of depression. Finally, we highlight the recent discovery that ketamine rapidly redistributes cholesterol in the plasmalemma of astrocytes, but not in fibroblasts nor in neuronal cells. This alteration of membrane structure may modulate a host of processes that synergistically contribute to ketamine's rapid and prominent antidepressant action.