Generalized anxiety disorder


Generalized anxiety disorder is an anxiety disorder characterized by excessive, uncontrollable, and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often, but not necessarily, overly concerned about everyday matters such as health, finances, death, family, relationship concerns, or work difficulties. Symptoms may include excessive worry, restlessness, trouble sleeping, exhaustion, irritability, sweating, and trembling.
Symptoms must be consistent and ongoing, persisting at least six months for a formal diagnosis. Individuals with GAD often have other disorders including other psychiatric disorders, substance use disorder, or obesity, and may have a history of trauma or family with GAD. Clinicians use screening tools such as the GAD-7 and GAD-2 questionnaires to determine if individuals may have GAD and warrant formal evaluation for the disorder. In addition, screening tools may enable clinicians to evaluate the severity of GAD symptoms.
Treatment includes types of psychotherapy and pharmacological intervention. CBT and selective serotonin reuptake inhibitors are first-line psychological and pharmacological treatments; other options include serotonin–norepinephrine reuptake inhibitors, and in more severe, last resort cases, benzodiazepines, though not as first-line drugs as benzodiazepines are frequently abused and habit forming. In Europe and the United States, pregabalin is also used. The potential effects of complementary and alternative medications, exercise, therapeutic massage, and other interventions have been studied. Brain stimulation, LSD, and other novel therapeutic interventions are also under study.
Genetic and environmental factors both contribute to GAD. A hereditary component influenced by brain structure and neurotransmitter function interacts with life stressors such as parenting style and abusive relationships. Emerging evidence also links problematic digital media use to increased anxiety. GAD involves heightened amygdala and prefrontal cortex activity, reflecting an overactive threat-response system. It affects about 2–6% of adults worldwide, usually begins in adolescence or early adulthood, is more common in women, and often recurs throughout life. GAD was defined as a separate diagnosis in 1980, with changing criteria over time that have complicated research and treatment development.

Causes

Genetics, family, and environment

The relationship between genetics and anxiety disorders is an ongoing area of research. It is broadly understood that there exists a hereditary basis for GAD, but the exact nature of this hereditary basis is not fully understood. While investigators have identified several genetic loci that are regions of interest for further study, there is no singular gene or set of genes that have been identified as causing GAD. Nevertheless, genetic factors may play a role in determining whether an individual is at greater risk for developing GAD, structural changes in the brain related to GAD, or whether an individual is more or less likely to respond to a particular treatment modality. Genetic factors that may play a role in development of GAD are usually discussed in view of environmental factors that might also play a role in development of GAD. The traditional methods of investigating the possible hereditary basis of GAD include using family studies and twin studies. Meta-analysis of family and twin studies suggests that there is strong evidence of a hereditary basis for GAD in that GAD is more likely to occur in first-degree relatives of individuals who have GAD than in non-related individuals in the same population. Twin studies also suggest that there may be a genetic linkage between GAD and major depressive disorder, which may explain the common occurrence of MDD in individuals who have GAD. When GAD is considered among all anxiety disorders, genetic studies suggest that hereditary contribution to the development of anxiety disorders amounts to only approximately 30–40%, which suggests that environmental factors are likely more important to determining whether an individual may develop GAD. In regard to environmental influences in the development of GAD, it has been suggested that parenting behaviour may be an important influence since parents potentially model anxiety-related behaviours. It has also been suggested that individuals with GAD have experienced a greater number of minor stress-related events in life and that the number of stress-related events may be important in development of GAD. Further research on the life context and social factors of individuals with GAD has provided greater insight into the influence of interpersonal relationships, with one study noting strong associations between partner abuse in women with the anxiety apparent in GAD. Thus, strained or stressful social relationships, as evidenced by abusive partners, display some association with the emergence of anxiety as a symptom of GAD.
Studies of possible genetic contributions to the development of GAD have examined relationships between genes implicated in brain structures involved in identifying potential threats and also implicated in neurotransmitters and neurotransmitter receptors known to be involved in anxiety disorders. More specifically, genes studied for their relationship to development of GAD or demonstrated to have had a relationship to treatment response include:
  • PACAP : remission after 6-month treatment with Venlafaxine suggested to have a significant relationship with the A54G polymorphism
  • HTR2A gene : HTR2A allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to six months of Venlafaxine treatment
  • SLC6A4 promoter region : Serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to six months of Venlafaxine treatment

    Problematic digital media use

Pathophysiology

The pathophysiology of GAD is an active and ongoing area of research, often involving the intersection of genetics and neurological structures. GAD has been linked to changes in functional connectivity of the amygdala and its processing of fear and anxiety. Sensory information enters the amygdala through the nuclei of the basolateral complex. The basolateral complex processes the sensory-related fear memories and communicates information regarding threat importance to memory and sensory processing elsewhere in the brain, such as the medial prefrontal cortex and sensory cortices. Neurological structures traditionally appreciated for their roles in anxiety include the amygdala, insula and orbitofrontal cortex. It is broadly postulated that changes in one or more of these neurological structures are believed to allow greater amygdala response to emotional stimuli in individuals who have GAD as compared to individuals who do not have GAD.
Individuals with GAD have been suggested to have greater amygdala and medial prefrontal cortex activation in response to stimuli than individuals who do not have GAD. However, the exact relationship between the amygdala and the frontal cortex is not fully understood because there are studies that suggest increased or decreased activity in the frontal cortex in individuals who have GAD. Consequently, because of the tenuous understanding of the frontal cortex as it relates to the amygdala in individuals who have GAD, it's an open question as to whether individuals who have GAD bear an amygdala that is more sensitive than an amygdala in an individual without GAD or whether frontal cortex hyperactivity is responsible for changes in amygdala responsiveness to various stimuli. Recent studies have attempted to identify specific regions of the frontal cortex that may be more or less reactive in individuals who have GAD or specific networks that may be differentially implicated in individuals who have GAD. Other lines of study investigate whether activation patterns vary in individuals who have GAD at different ages with respect to individuals who do not have GAD at the same age.

Evolutionary Explanations

From an evolutionary perspective, generalized anxiety can be viewed as an overextension of the protective mechanisms that help organisms avoid danger. Cost–benefit analyses, sometimes referred to as the "smoke detector principle," propose that false alarms are less costly than failing to detect real threats. As a result, having a relatively low threshold for perceiving danger may have historically conferred survival benefits. In individuals with GAD, however, this adaptive threshold appears to be set too low or activated too often, generating pervasive worry about routine events and relatively minor stressors.
Empirical work supports the idea that GAD involves heightened reactivity in brain regions associated with threat detection, including the amygdala. Researchers have also found links between GAD and elevated inflammation markers, suggesting a possible physiological correlate for the chronic anxiety seen in the disorder. Although anxiety's defensive functions may have been advantageous in unpredictable environments, modern contexts can render this vigilance maladaptive when it persists as near-constant worry and avoidance. This view places GAD at the extreme end of a continuum, where otherwise beneficial anxiety responses overshoot, leading to significant distress and functional impairment.

Diagnosis

DSM-5 criteria

The diagnostic criteria for GAD as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, published by the American Psychiatric Association, are paraphrased as follows:No major changes to GAD have occurred since publication of the Diagnostic and Statistical Manual of Mental Disorders ; minor changes include wording of diagnostic criteria.

ICD-10 criteria

The 10th revision of the International Statistical Classification of Diseases provides a different set of diagnostic criteria for GAD than the DSM-5 criteria described above. In particular, ICD-10 allows diagnosis of GAD as follows:
Note: For children different ICD-10 criteria may be applied for diagnosing GAD.