Anxiety disorders

Abstract

Anxiety disorders constitute the largest group of mental disorders in most western societies and are a leading cause of disability. The essential features of anxiety disorders are excessive and enduring fear, anxiety or avoidance of perceived threats, and can also include panic attacks. Although the neurobiology of individual anxiety disorders is largely unknown, some generalizations have been identified for most disorders, such as alterations in the limbic system, dysfunction of the hypothalamic-pituitary-adrenal axis and genetic factors. In addition, general risk factors for anxiety disorders include female sex and a family history of anxiety, although disorder-specific risk factors have also been identified. The diagnostic criteria for anxiety disorders varies for the individual disorders, but are generally similar across the two most common classification systems: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, Tenth Edition (ICD-10). Despite their public health significance, the vast majority of anxiety disorders remain undetected and untreated by health care systems, even in economically advanced countries. If untreated, these disorders are usually chronic with waxing and waning symptoms. Impairments associated with anxiety disorders range from limitations in role functioning to severe disabilities, such as the patient being unable to leave their home.

Figure 1 |. Anxiety disorders.

Several individual disorders can be classified under the broad heading of anxiety disorders. Although these disorders can present throughout life, some individual disorders have specific ages of onset. For example, most cases of separation anxiety and specific phobias develop in childhood, and most cases of social anxiety disorder develop in adolescence or early adulthood. In addition, the age at onset for panic disorder, agoraphobia and generalized anxiety disorder tends to vary but is typically early in adulthood, although generalized anxiety disorder can occur for the first time later in life^,. Although previously listed under the anxiety disorder Diagnostic and Statistical Manual of Mental Disorders (DSM) classification, obsessive–compulsive disorder and post-traumatic stress disorder are no longer classified as such and are in separate categories in the DSM-5 (indicated by dashed arrows).

Figure 2 |. Prevalence and sex ratio of anxiety disorders.

The 12-month prevalence estimate of anxiety disorders in 14 European countries is 14%, meaning that 61.5 million individuals in Europe alone have had an anxiety disorder in the past 12 months. Within the anxiety disorders, the 12-month prevalence for specific phobia is higher than the other disorders. In general, anxiety disorders are at least twice as common in women as in men. Error bars represent the range in prevalence estimates across the 14 countries. Data from REF. .

Figure 3 |. Key brain regions involved in the generation and regulation of emotions and threat detection.

In this model, amygdala-driven fear and anxiety are regulated through bidirectional connections to the ventromedial prefrontal cortex (vmPFC) and the anterior cingulate cortex (ACC), along with functional crosstalk between these regions and the hippocampus^,,. This model translates across species and fits well with observations in patients. For example, differences in the degree and coordination of amygdala, vmPFC and hippocampus activity correlate with how well mice, rats or humans can suppress anxiety, extinguish fear and avoid cognitive bias to potential threat^,,. Notably, consistent with the crucial contribution of the amygdala to the formation and expression of conditioned fear memories in rodents^,,, amygdala hyperactivation along with diminished vmPFC activity to threat cues have repeatedly been found in patients, albeit mainly patients with post-traumatic stress disorder (PTSD) and with exceptions in certain symptomatically distinct populations. In addition, functional connectivity between the amygdala, hippocampus and vmPFC, and the dorsal ACC and anterior insula is deficient in PTSD^,,,. Interestingly, normalization of these disturbances parallels the symptom attenuation observed with cognitive–behavioural therapy in social anxiety disorder^,.

Figure 4 |. Symptom progression model of anxiety disorders.

a | Symptom progression models describe the developmental pathways of vulnerability and risk factors over time that are typical of the expression of subclinical and transient early signs, the onset of the clinical disorder and the typical onset of complications and comorbidities associated with a persistent course of the disorder, if untreated. For anxiety disorders, broadly speaking, three main symptom onsets can be identified: subthreshold anxiety symptoms (trajectory 1), threshold anxiety disorders (trajectory 2) and secondary complications and comorbidities (trajectory 3). b | Targeted preventive therapies in the preclinical stages of anxiety could reduce the prevalence of clinically relevant anxiety disorders (black arrows). Targeted interventions after the onset of the disorder, such as cognitive–behavioural therapy, could reduce the severity of complications (blue arrows). Adapted with permission from REF. , Elsevier.

Figure 5 |. Disability-adjusted life years lost for mental disorders, neurological disorders and other disease groups.

a | The total distribution (%) of disability-adjusted life years (DALYs) that are attributable to mental and neurological disorders, in addition to other somatic diseases and conditions. b | The DALYs for different disorders. OCD, obsessive–compulsive disorder; PTSD, post-traumatic stress disorder. *This value is a conservative estimate and does not reflect the total burden, because comorbid anxiety–depression cases are counted entirely towards depression. Data from REF. .