Abstract
There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.
Highlights
Anxiety disorders constitute one of the most prevalent classes of psychiatric disorders
obsessive compulsive disorder (OCD) and post-traumatic stress disorder (PTSD) are quite different with regard to their symptomatology compared to generalized anxiety disorder (GAD) or social phobia
We argue that by using translational preclinical models, anxiety-related genes can be mapped and this information may subsequently be used to enhance our understanding of clinical studies in order to identify novel drug targets for anxiety
Summary
Anxiety disorders constitute one of the most prevalent classes of psychiatric disorders. Anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) include panic disorder (PD), generalized anxiety disorder (GAD), phobias, social phobia, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) and were the most common mental disorders within Europe in 2010 with 14% prevalence (Wittchen, 2011). The heterogeneous classification system of individual anxiety disorders in the DSM-IV is based on symptomatology rather than etiology (Friedman et al, 2011). Specific anxiety disorders are often incomparable to each other with regard to the symptomatology. OCD and PTSD are quite different with regard to their symptomatology compared to GAD or social phobia. Application of the DSM-V has not resulted in major changes in the classification of anxiety disorders (Friedman et al, 2011). A classification based on the neurobiological mechanisms underlying pathological anxiety (intermediate phenotypes) www.frontiersin.org
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