Clinical features and genetic mechanisms of anxiety, fear, and avoidance: A comprehensive review of five anxiety disorders

Abstract Anxiety disorders, including social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), agoraphobia (AG), and specific phobia (SP), are characterized by core features of excessive anxiety and fear. Furthermore, these disorders are often accompanied by avoidance behaviors. While avoidance is a common behavioral response, it may be a consequence of or a cocontributor to the anxiety and fear driving these disorders. This narrative review integrates the interactions among anxiety, fear, and avoidance behaviors across these five disorders and synthesizes findings from clinical, neuropsychological, brain function, treatment, genetic, and epigenetic studies. Based on the intensity of anxiety and fear, these anxiety five disorders can be categorized into three groups: fear-dominant (SP, AG), mixed (PD, SAD), and anxiety-dominant (GAD). The intensity of avoidance behaviors is related to the age of onset. Each group responds to different treatment approaches. In fear-dominant disorders, exposure therapy is highly effective in reducing avoidance behaviors and fear responses. Cognitive behavioral therapy (CBT) with an emphasis on exposure is useful. In the mixed group, CBT is the preferred treatment, with a focus on both exposure therapy and cognitive restructuring. In addition to CBT, selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) are commonly used to reduce anticipatory anxiety and fear symptoms. In anxiety-dominant disorders, both SSRIs/SNRIs and CBT with an emphasis on cognitive restructuring are effective for managing chronic worry. Anxiety and fear are regulated by distinct but interacting neurobiological mechanisms, with the amygdala central to fear processing and the hypothalamic‒pituitary‒adrenal axis involved in chronic anxiety regulation. Genetic and epigenetic studies demonstrate substantial heritability across anxiety disorders, with varying degrees of genetic influence on anxiety, fear, and avoidance. Avoidance behaviors, particularly in early-onset disorders such as SP and SAD, may be more strongly influenced by genetic factors. Large-scale genome-wide association studies (GWASs) grouping anxiety disorders have identified shared genetic loci, but GWASs for individual anxiety disorders are limited by small sample sizes. Grouping anxiety disorders into broader categories – namely, fear-dominant, mixed, and anxiety-dominant – rather than considering each specific anxiety disorder in isolation may lead to increased statistical power and yield more comprehensive perspectives on the shared and distinct clinical and genetic risk factors among anxiety disorders.