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Although anxious depression is known to be associated with poor treatment outcomes in several studies, recent researches have sought to find better treatment strategy to improve patients with anxious depression.The present chapter is an overview of possible biomarkers which distinguish anxiety disorders as classified by the DSM-5. Structural or activity changes in the brain regions; changes in N-acetylaspartate/creatine, dopamine, serotonin, and oxytocin; hearth rate variability; hypothalamic-pituitary-adrenal axis activity; error-related negativity; respiratory regulation; and genetic variants are proposed. However, their clinical utility is questionable due to low specificity and sensitivity the majority does not distinguish subjects with different anxiety disorders, and they might be influenced by stress, comorbidity, physical activity, and psychotropic medications. In this framework, the staging model, a clinimetric tool which allows to define the degree of progression of a disease at a point in time and where the patient is located on the continuum of the course of the disease, is proposed since several DSM anxiety disorders take place at different stages of the same syndrome according to the staging model. Thus, a stage-specific biomarker model for anxiety disorders is hypothesized and illustrated.Under the partial influences of paradigm shift form category to dimension, the Diagnostic and Statistical Manual of Mental Disorder (DSM) was revised to the fifth edition (DSM-5); however, due to the lack of consistent biological makers and processes and the restricted availability of dimensional meta-structure, the revisions for the DSM-5 were based on a combination of categorical and dimensional approaches. Anxiety disorders were more clearly and consistently defined in the DSM-5 with the removal of obsessive compulsive, acute stress, and post-traumatic stress disorders. Differences between the childhood and adulthood categories of anxiety disorders were decreased, and overall, the symmetrical classification of anxiety subtypes was increased, since separation anxiety disorder and selective mutism were considered anxiety disorders, not neurodevelopmental disorders. Additionally, based on growing evidence, agoraphobia is distinct from panic disorder. Next, considering cultural syndromes including taijin kyofusho, khyal cap, trung gio attacks, and ataque de nervios, cultural influences are considered a significant factor for definitions and presentations of anxiety disorders. Controversies in the DSM-5 criteria for anxiety disorders are lowering the diagnostic thresholds of anxiety disorders and limiting the dichotomous view of anxiety and depression when defining generalized anxiety disorder. Further studies of alternative approaches to the restrictions of the DSM-5 criteria of anxiety disorders, including transdiagnostic specifiers and dimensional assessment tools, may be required.This chapter describes the various animal models that seem relevant to the development of anxiolytic drugs, as well as the human models of induced anxiety, or more precisely the panic inducers including cholecystokinin. It is also mentioned the theoretical model of Deakin and Graeff which seems to keep all its relevance. The knock animals are evoked as relevant tools as well as a new optogenetic technique that needs to be used in this field.Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body's serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.Substantial evidence from various studies suggests a preeminent role for early adverse experiences in the development of psychopathology. The most recent studies reviewed here suggest that early life stressors are associated with an increased risk for anxiety disorders in adulthood. Early life stress predisposes individuals to develop a number of psychiatric syndromes, particularly affective disorders, including anxiety disorders, and is therefore a significant health problem.This review examines the emerging literature on the relationship between stress, hypothalamic-pituitary-adrenal (HPA) axis function, and generalized anxiety disorder (GAD), panic disorder, and phobias and the role of early life stress as an important risk factor for HPA axis dysfunction.The most consistent findings in the literature show increased activity of the HPA axis in depression associated with hypercortisolemia and reduced inhibitory feedback. In addition to melancholic depression, a spectrum of other conditions may be associated of the stress response and thus of the HPA axis that can endure during adulthood, predisposing individuals to develop psychopathology.Discovery of innovative anxiolytics is severely hampering. Existing anxiolytics are developed decades ago and are still the therapeutics of choice. Moreover, lack of new drug targets forecasts a severe jeopardy in the future treatment of the huge population of CNS-diseased patients. We simply lack the knowledge on what is wrong in brains of anxious people (normal and diseased). Translational research, based on interacting clinical and preclinical research, is extremely urgent. In this endeavor, genetic and genomic approaches are part of the spectrum of contributing factors. We focus on three druggable targets serotonin transporter, 5-HT1A, and GABAA receptors. It is still uncertain whether and how these targets are involved in normal and diseased anxiety processes. [https://www.selleckchem.com/products/Menadione.html https://www.selleckchem.com/products/Menadione.html] For serotonergic anxiolytics, the slow onset of action points to indirect effects leading to plasticity changes in brain systems leading to reduced anxiety. For GABAA benzodiazepine drugs, acute anxiolytic effects are found indicating primary mechanisms directly influencing anxiety processes.