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Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

The present study was undertaken to investigate the regulatory mechanisms of fibroblast growth factor-1 and -2 (FGF-1 and FGF-2) gene expression compared with ciliary neurotropic factor (CNTF) in rat cortical astrocytes. Glial cells represent a source of different trophic factors and cytokines that can influence the survival of multiple cell populations within the central nervous system. We found that the beta-adrenergic receptor agonist (betaAR) isoproterenol produced a significant induction of FGF-2 gene expression and protein in type I astrocytes. On the contrary, the gene expression for FGF-1 and CNTF is markedly reduced after exposure to isoproterenol. The changes produced by the beta AR agonist is mimicked by cyclic AMP analogues (8-bromo-cAMP) or 3-isobutyl-1-methyl-xanthine, a cAMP phosphodiesterase inhibitor, which indicates that intracellular elevation of this second messenger is responsible for these effects. The regulation of neurotrophic factors by isoproterenol is not restricted to cortical astrocytes and may take place through different mechanisms. Inhibition of protein synthesis prevents the decrease in CNTF without affecting the changes in FGF-1 and FGF-2 gene expression. Coincubation of isoproterenol with actinomycin D, an inhibitor of gene transcription, prevents the modification of neurotrophic factor biosynthesis, indicating that transcriptional mechanisms are indeed involved in these regulatory pathways. However, the determination of FGF-2 mRNA half-life suggests that the effect of the betaAR agonist can be in part the result of mRNA stabilization. The mechanisms that we describe can be important in the maintenance of neuronal homeostasis and may be relevant in the development of alternative strategies for the treatment of acute and chronic neurodegenerative disorders

The Advisory Committee on Immunization Practices recommends that all pregnant women be questioned concerning risk factors for hepatitis B virus infection and that those giving positive responses be serotested. The sensitivity, specificity, and predictive value of those recommended questions among 692 parturient women were determined. A total of 59 currently or previously infected women (hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), or antibody to hepatitis B core antigen (anti-HBc) seropositive) were compared with the 633 seronegative women. Among nonwhite women, the sensitivity of a positive response to any one of the recommended questions was 60%. Specificity and positive predictive value were 71% and 19%, respectively. Among white women, the sensitivity, specificity, and positive predictive value were 56%, 75%, and 11%, respectively. To increase such unacceptably low sensitivity, the authors included two additional questions: single marital status and Medicaid/medical assistance payer status. Sensitivity increased to 96% among nonwhite women and 84% among white women. However, a positive response to at least one of the recommended questions or to additional questions was elicited from 78% of all women (92% nonwhite and 64% white). The authors conclude that to prevent perinatal transmission of hepatitis B, we must serotest all women in our obstetric population.