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Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma–dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.

BackgroundPregnancy is a time of increased vulnerability for the development of anxiety and depression. This systematic review aims to identify the main risk factors involved in the onset of antenatal anxiety and depression.MethodsA systematic literature analysis was conducted, using PubMed, PsychINFO, and the Cochrane Library. Original papers were included if they were written in English and published between 1st January 2003 and 31st August 2015, while literature reviews and meta-analyses were consulted regardless of publication date. A final number of 97 papers were selected.ResultsThe most relevant factors associated with antenatal depression or anxiety were: lack of partner or of social support; history of abuse or of domestic violence; personal history of mental illness; unplanned or unwanted pregnancy; adverse events in life and high perceived stress; present/past pregnancy complications; and pregnancy loss.LimitationsThe review does not include a meta-analysis, which may have added additional information about the differential impact of each risk factor. Moreover, it does not specifically examine factors that may influence different types of anxiety disorders, or the recurrence or persistence of depression or anxiety from pregnancy to the postpartum period.ConclusionsThe results show the complex aetiology of antenatal depression and anxiety. The administration of a screening tool to identify women at risk of anxiety and depression during pregnancy should be universal practice in order to promote the long-term wellbeing of mothers and babies, and the knowledge of specific risk factors may help creating such screening tool targeting women at higher risk.

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Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.