generalized anxiety disorder generalized anxiety disorder generalized anxiety disorder (gad) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. worry often interferes with daily functioning, and individuals with gad are often 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. generalized anxiety disorderother namesgeneralised anxiety disorderillustration of a female psychiatric patient with gadspecialtypsychiatry, psychology symptomsexcessive worry, restlessness, trouble sleeping, feeling tired, irritability, sweating, tremblingcomplicationsdepression, heart disease, suicidetreatmentbehavioral therapy, metacognitive therapy, medicationsfrequency3–5% (lifetime prevalence) symptoms must be consistent and ongoing, persisting at least six months, for a formal diagnosis of gad. individuals with gad often have other disorders including other psychiatric disorders (e.g., major depressive disorder), substance use disorder, 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. additionally, sometimes screening tools may enable clinicians to evaluate the severity of gad symptoms. gad is believed to have a hereditary or genetic basis (e.g., first-degree relatives of an individual who has gad are themselves more likely to have gad), but the exact nature of this relationship is not fully appreciated. genetic studies of individuals who have anxiety disorders (including gad) suggest that the hereditary contribution to developing anxiety disorders is only approximately 30–40%, which suggests that environmental factors may be more important to determining whether an individual develops gad. there is a strong overlapping relationship between gad and major depressive disorder (mdd) with 72% of those with a lifelong diagnosis of gad also being diagnosed with mdd at some point in their life. the pathophysiology of gad implicates several regions of the brain that mediate the processing of stimuli associated with fear, anxiety, memory, and emotion (i.e., the amygdala, insula and the frontal cortex). the amygdala is part of the brain that is associated with experiencing emotions. in the amygdala, the basolateral amygdala complex recognizes sensory information and activates gabaergic neurons which can cause somatic symptoms of anxiety. gabaergic neurons control the nervous system by reducing feelings of stress, anxiety, and fear. when there is an inadequate number of gabaergic neurons, those negative feelings become apparent and can release somatic responses of stress. it has been suggested that individuals with gad have greater amygdala and medial prefrontal cortex (mpfc) activity in response to stimuli than individuals who do not have gad. however, the relationship between gad and activity levels in other parts of the frontal cortex is the subject of ongoing research with some literature suggesting greater activation in specific regions for individuals who have gad but where other research suggests decreased activation levels in individuals who have gad as compared to individuals who do not have gad. treatment includes psychotherapy, e.g. cognitive behavioral therapy (cbt) or metacognitive therapy, and pharmacological intervention (e.g., citalopram, escitalopram, sertraline, duloxetine, and venlafaxine). cbt and selective serotonin reuptake inhibitors (ssris) are first-line psychological and pharmacological treatments; other options include selective norepinephrine reuptake inhibitors (snris). in europe, pregabalin is also used. the positive effects (if any) of complementary and alternative medications (cams), exercise, therapeutic massage and other interventions have been studied. estimates regarding prevalence of gad or lifetime risk (i.e., lifetime morbid risk (lmr)) for gad vary depending upon which criteria are used for diagnosing gad (e.g., dsm-5 vs icd-10) although estimates do not vary widely between diagnostic criteria. in general, icd-10 is more inclusive than dsm-5, so estimates regarding prevalence and lifetime risk tend to be greater using icd-10. in regard to prevalence, in a given year, about two (2%) percent of adults in the united states and europe have been suggested to have gad. however, the risk of developing gad at any point in life has been estimated at 9.0%. although it is possible to experience a single episode of gad during one's life, most people who experience gad experience it repeatedly over the course of their lives as a chronic or ongoing condition. gad is diagnosed twice as frequently in women as in men. diagnosis dsm-5 criteria the diagnostic criteria for gad as defined by the diagnostic and statistical manual of mental disorders dsm-5 (2013), published by the american psychiatric association, are paraphrased as follows:"excessive anxiety or worry" experienced most days over at least six months and which involve a plurality of concerns.inability to manage worry.at least three of the following occur: restlessnessfatigabilityproblems concentratingirritabilitymuscle tensiondifficulty with sleep note that in children, only one of the above items is required.one experiences significant distress in functioning (e.g., work, school, social life).symptoms are not due to a substance use disorder, prescription medication, or other medical condition(s).symptoms do not fit better with another psychiatric condition such as panic disorder.no major changes to gad have occurred since publication of the diagnostic and statistical manual of mental disorders (2004); minor changes include wording of diagnostic criteria. icd-10 criteria the 10th revision of the international statistical classification of disease (icd-10) 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: a period of at least six months with prominent tension, worry, and feelings of apprehension, about everyday events and problems.at least four symptoms out of the following list of items must be present, of which at least one from items (1) to (4). autonomic arousal symptoms (1) palpitations or pounding heart, or accelerated heart rate. (2) sweating. (3) trembling or shaking. (4) dry mouth (not due to medication or dehydration). symptoms concerning chest and abdomen (5) difficulty breathing. (6) feeling of choking. (7) chest pain or discomfort. (8) nausea or abdominal distress (e.g. churning in the stomach). symptoms concerning brain and mind (9) feeling dizzy, unsteady, faint or light-headed. (10) feelings that objects are unreal (derealization), or that one's self is distant or "not really here" (depersonalization). (11) fear of losing control, going crazy, or passing out. (12) fear of dying. general symptoms (13) hot flashes or cold chills. (14) numbness or tingling sensations. symptoms of tension (15) muscle tension or aches and pains. (16) restlessness and inability to relax. (17) feeling keyed up, or on edge, or of mental tension. (18) a sensation of a lump in the throat or difficulty with swallowing. other non-specific symptoms (19) exaggerated response to minor surprises or being startled. (20) difficulty in concentrating or mind going blank, because of worrying or anxiety. (21) persistent irritability. (22) difficulty getting to sleep because of worrying.the disorder does not meet the criteria for panic disorder (f41.0), phobic anxiety disorders (f40.-), obsessive-compulsive disorder (f42.-) or hypochondriacal disorder (f45.2).most commonly used exclusion criteria: not sustained by a physical disorder, such as hyperthyroidism, an organic mental disorder (f0) or psychoactive substance-related disorder (f1), such as excess consumption of amphetamine-like substances, or withdrawal from benzodiazepines.see icd-10 f41.1 note: for children different icd-10 criteria may be applied for diagnosing gad (see f93.80). history of diagnostic criteria the american psychiatric association introduced gad as a diagnosis in the dsm-iii in 1980, when anxiety neurosis was split into gad and panic disorder. the definition in the dsm-iii required uncontrollable and diffuse anxiety or worry that is excessive and unrealistic and persists for 1 month or longer. high rates in comorbidity of gad and major depression led many commentators to suggest that gad would be better conceptualized as an aspect of major depression instead of an independent disorder. many critics stated that the diagnostic features of this disorder were not well established until the dsm-iii-r. since comorbidity of gad and other disorders decreased with time, the dsm-iii-r changed the time requirement for a gad diagnosis to 6 months or longer. the dsm-iv changed the definition of excessive worry and the number of associated psychophysiological symptoms required for a diagnosis. another aspect of the diagnosis the dsm-iv clarified was what constitutes a symptom as occurring "often". the dsm-iv also required difficulty controlling the worry to be diagnosed with gad. the dsm-5 emphasized that excessive worrying had to occur more days than not and on a number of different topics. it has been stated that the constant changes in the diagnostic features of the disorder have made assessing epidemiological statistics such as prevalence and incidence difficult, as well as increasing the difficulty for researchers in identifying the biological and psychological underpinnings of the disorder. consequently, making specialized medications for the disorder is more difficult as well. this has led to the continuation of gad being medicated heavily with ssris. risk factors 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 (e.g., life experience or ongoing stress) 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 (there are no known adoption studies of individuals who have anxiety disorders, including gad). 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 (mdd), which may explain the common occurrence of mdd in individuals who have gad (e.g., comorbidity of mdd in individuals with gad has been estimated at 60%). when gad is considered among all anxiety disorders (e.g., panic disorder, social anxiety disorder), 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 (irrespective of other individual characteristics). studies of possible genetic contributions to the development of gad have examined relationships between genes implicated in brain structures involved in identifying potential threats (e.g., in the amygdala) 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 (a54g polymorphism): remission after 6-month treatment with venlafaxine suggested to have a significant relationship with the a54g polymorphism (cooper et al. (2013)) htr2a gene (rs7997012 snp g allele): htr2a allele suggested to be implicated in a significant decrease in anxiety symptoms associated with response to 6 months of venlafaxine treatment (lohoff et al. (2013)) slc6a4 promoter region (5-httlpr): serotonin transporter gene suggested to be implicated in significant reduction in anxiety symptoms in response to 6 months of venlafaxine treatment (lohoff et al. (2013)) pathophysiology amygdala (in red) brain structures linked to anxiety disorders the pathophysiology of gad is an active and ongoing area of research often involving the intersection of genetics and neurological structures. generalized anxiety disorder 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 (consisting of lateral, basal and accessory basal nuclei). the basolateral complex processes the