INTRODUCTION — Generalized anxiety disorder (GAD) is characterized by excessive and persistent worrying that is hard to control, causes significant distress or impairment, and occurs on more days than not for at least six months. Other features include psychological symptoms of anxiety, such as apprehensiveness and irritability, and physical (or somatic) symptoms of anxiety, such as increased fatigue and muscular tension.

Effective treatments for GAD include psychological interventions such as cognitive-behavioral therapy and applied relaxation, and medications including selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors.

This topic addresses the epidemiology, pathogenesis, clinical manifestations, and diagnosis of GAD. Pharmacotherapy and psychotherapy for GAD are discussed separately:

●(See "Generalized anxiety disorder in adults: Management".)

●(See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies".)

EPIDEMIOLOGY

Prevalence — GAD is one of the most common mental disorders in both community and clinical settings. It is associated with increased use of health care services [1].

Epidemiologic studies of nationally representative samples in the United States have found a lifetime prevalence of GAD of 5.1 percent [2,3] to 11.9 percent [4]. A review of epidemiological studies in Europe found a 12-month prevalence of 1.7 to 3.4 percent [5], and a lifetime prevalence of 4.3 to 5.9 percent [6].

The disorder is approximately twice as common in women as it is in men [2,4].

Risk for late-onset GAD — GAD is likely the most common anxiety disorder among the older adult population [5,7]. Late-onset GAD is usually associated with certain demographic, clinical, and environmental risk factors [8,9]. (See 'Onset' below.)

Predictors of late-onset GAD include:

●Female sex

●Poverty

●Recent adverse life events

●Chronic physical illness (respiratory, cardiovascular, metabolic, cognitive)

●Chronic mental disorder (depression, phobia, and past GAD)

●Parental loss or separation

●Low affective support during childhood

●History of mental problems in parents

Comorbidity — Comorbidity with major depression or other anxiety disorders has been observed in the majority of cases of GAD [5]. In a nationally representative survey of United States adults, 66 percent of individuals with current GAD had at least one concurrent disorder [2]. Individual disorders found to co-occur in people with GAD (rates over the previous 30 days and lifetime) included [2,10]:

●Major depression – 39 and 62 percent

●Social phobia – 23 and 34 percent

●Specific phobia – 25 and 35 percent

●Panic disorder – 23 and 24 percent

GAD may also be associated with increased rates of substance abuse, posttraumatic stress disorder, and obsessive-compulsive disorder.

Patients with comorbid major depression and GAD tended to have a more severe and prolonged course of illness and greater functional impairment [11]. The presence of comorbid major depressive episodes is associated with a poorer prognosis in patients with GAD. The National Comorbidity Survey follow-up study found that patients with comorbid GAD and major depression were significantly more likely to fulfil criteria for GAD 10 years later [4].

GAD is common among patients with “medically unexplained” chronic pain [12] and with chronic physical illness [13]. (See 'Course' below.)

●(See "Unipolar depression in adults: Epidemiology".)

●(See "Social anxiety disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)

●(See "Specific phobia in adults: Epidemiology, clinical manifestations, course and diagnosis".)

●(See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)

●(See "Risky drinking and alcohol use disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

●(See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis".)

●(See "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".)

PATHOGENESIS

Biological factors

Genetics — Genetic factors appear to predispose individuals to the development of GAD, although data from twin studies have been inconsistent. GAD shares a common heritability with major depression [14] and with the personality trait of “neuroticism” [15,16]. The serotonin transporter gene-linked polymorphic region SS genotype (short/short) has been found to be more frequent in patients with GAD [17]. Variations in two sub-types of the glutamic acid decarboxylase gene may increase individual susceptibility to anxiety disorders, including GAD [18,19]. Gene-environment studies have highlighted the importance of early developmental trauma and recent stressful life events and their interaction with genetic markers in the development of GAD, trait anxiety, and anxiety sensitivity [20].

Neurotransmitter and other biomarker disturbances — Investigations of potential disturbances in the principal neurotransmitters norepinephrine, 5-hydroxtryptamine (5-HT, serotonin) and gamma aminobutyric acid in GAD have tended to be small, inconsistent, or unreplicated.

Examples include:

●Studies have suggested the levels of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylgycol and vanillylmandelic acid are increased in patients with GAD [21,22].

●The growth hormone response to clonidine challenge has been found to be blunted, suggesting decreased postsynaptic alpha-2 adrenergic receptor sensitivity [23].

●Elevated urinary levels of the serotonin metabolite 5-hydroxyindoleacetic acid were shown in one study to be associated with greater somatic anxiety symptoms, but not psychic anxiety symptoms [22].

●Benzodiazepine binding sites on platelets and lymphocytes are reduced in density in patients with GAD, but increase in density after administration of diazepam [24,25].

●Provocation studies involving 7.5 percent carbon dioxide inhalation in small samples of healthy volunteers suggest the involvement of acid-sensing ion channels in the amygdala in autonomic and other symptoms and induced worrying [26].

●C-reactive protein levels are elevated in patients with GAD, and levels of proinflammatory cytokines may also be raised, but it is unclear whether inflammatory disturbances play a causative role [27].

Changes in brain metabolism — Changes in glucose metabolism in the cortex, limbic system, and basal ganglia are suggestive of their role in the development of anxiety. As examples:

●A study of positron emission tomography scans in patients with GAD demonstrated a relative increase in glucose metabolism in parts of the occipital, right posterior temporal lobe, inferior gyrus, cerebellum and right frontal gyrus, and an absolute decrease in the basal ganglia. Benzodiazepine administration was associated with decreases in absolute metabolic rates for cortical surface, limbic system and basal ganglia, but was not associated with normalization of patterns of glucose metabolism [28].

●A functional magnetic resonance imaging study found increased post cue anticipatory activity bilaterally in the dorsal amygdala, after cues indicating forthcoming neutral and aversive pictures, providing evidence of overall enhanced anticipatory emotional responsiveness in GAD [29].

Cognitive, psychological, and developmental factors

Processing of emotional information — Investigations of the processing of emotional information suggest that GAD may be associated with specific biases for mood-congruent information [30]. Patients with GAD have been found to allocate extensive attentional resources to threatening stimuli, detect “threats” rapidly and effectively [31], and misinterpret ambiguous information as being threatening [32], particularly when visual threat material is in verbal-linguistic format [33]. These biases diminished with successful treatment with cognitive-behavioral therapy [34] or a selective serotonin reuptake inhibitor [35].

Developmental and personality factors — GAD in adult life is associated with a higher-than-average number of traumatic experiences and other undesirable life events in childhood, compared to individuals without GAD [36]. GAD is more likely to occur in people with “behavioral inhibition,” which is the tendency to be timid and shy in novel situations [37]. The personality trait of “neuroticism” (or negative affectivity) is associated with comorbid GAD and major depression [38,39].

Cognitive origins of excessive worrying — Many explanations of the origin and persistence of the excessive and pervasive worrying that characterize GAD have been proposed. As examples, affected individuals may:

●Constantly scan the environment for cues of threat [40]

●Develop worrying in an attempt to solve problems [41]

●Use worrying to avoid the fear response [42]

●Have intolerance of uncertainty or ambiguity [43]

●Worry about the uncontrollability and presumed dangerous consequences of worrying [44]

CLINICAL MANIFESTATIONS — Although excessive and persistent worrying is widely regarded as the pathognomonic feature of GAD, most patients present with other symptoms relating to hyperarousal, autonomic hyperactivity and muscle tension.

Many patients complain of poor sleep, fatigue and difficulty relaxing. Headaches and pain in the neck, shoulders, and back are commonly reported. It is common for patients with these symptoms to present to health professionals repeatedly, with pressing but long-standing concerns that prove to be medically unexplained.

The nature of excessive and persistent worrying has not been investigated extensively. Individuals with GAD have reported a greater number of worries, but were found to share the same concerns about health, family and interpersonal relationships, work and finances as nonanxious controls [45]. Individuals with GAD have been distinguished from controls, and from patients with other anxiety disorders, by having greater worry over minor matters [45]. Patients with GAD typically respond positively to the question, “Do you worry excessively about minor matters?”, while a negative response should rule out the diagnosis of GAD [46].

COURSE — GAD is considered to be a chronic illness with fluctuating symptom severity. Longitudinal studies in treatment-seeking patients generally provide evidence supporting this course of the illness. For example, a prospective study of 179 patients with GAD (the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised [DSM-III-R]) in the United States found that approximately 60 percent of patients recovered over 12 years (ie, had no more than residual symptoms for eight consecutive weeks), but approximately one-half of recovered patients subsequently relapsed during the 12-year period [47] The decline in mean anxiety symptom severity in the patients with GAD was only modest [48].

Onset — GAD typically has a gradual onset [49] with emergence [49] of the full syndromal disorder later than some other anxiety disorders. Sub-syndromal anxiety symptoms are common before the age of 20 years [50]. Patients with an early age of onset tend to have a more protracted course and present with comorbid depression or other disorders [51].

GAD is common in older adults. Late-onset GAD is likely the most common anxiety disorder among the older adult population [5,7].

Outcome — GAD is associated with a significant degree of functional impairment. The level of functional impairment has been found to be similar to individuals with major depression [52,53]. However, studies of individuals with GAD in community samples suggest a better prognosis than studies of clinical populations. A 22-year follow-up study of 105 community living individuals meeting the Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) criteria for GAD found that less than 20 percent had persistent GAD (defined by the presence of daily symptoms over the previous 12 months) [50].

GAD is associated with poor cardiovascular health, coronary heart disease [54], and cardiovascular mortality [55]. Conclusions drawn from studies of this relationship include:

●Excessive worry has been associated with diminished heart rate variability and elevated heart rate

●Worrying and GAD have been commonly associated with increased blood pressure, diagnosed hypertension, and antihypertensive use in both disease-free patients and those with coronary heart disease

●Greater severity of worry has been associated with higher rates of fatal and nonfatal coronary heart disease, independent of the presence or severity of depression

●No evidence has been found to support the contention that worry might be beneficial for health promoting behaviors

Prospective studies suggest that clinically significant anxiety in the midlife period may be an independent risk factor for the development of dementia [56].

ASSESSMENT — The diagnosis of GAD can be challenging as the symptoms may be suggestive of other diagnoses such as mood disorders or medical conditions. Assessment of a patient with possible GAD should include a careful review of symptoms suggestive of GAD as well as a detailed history of possible co-occurring or alternative medical or psychiatric disorders, including substance use disorders.

In older individuals, the common co-occurrence of long-term physical illnesses, chronic insomnia, cognitive impairment, and the side effects of prescribed medication can make the diagnosis more difficult. Additionally, older adult patients with GAD may assert that anxiety or fear is a realistic response to their social environment, recent life events, and current challenges; questions that may be helpful in their assessment include:

●“How do you feel in times of stress?”

●“How good are you in controlling any worries?”

Those who have findings suggesting a possible physical cause of anxiety symptoms (eg, patients with late-onset anxiety, with weight loss, or with cognitive impairment) should undergo a physical examination and have laboratory studies to rule out organic causes of anxiety.

Laboratory studies should include complete blood count, chemistry panel, serum thyrotropin, urinalysis, electrocardiogram (in patients over 40 with chest pain or palpitations), or urine or serum toxicology analysis for drugs or medications. (See 'Differential diagnosis' below and 'Comorbidity' above.)

Screening instrument — The GAD seven-item (GAD-7) scale (calculator 1) can be used to screen for GAD in primary care. It has been found to have acceptable reliability and criterion, construct, factorial and procedural validity [57]. The GAD-7 has been found to be sensitive to change and can be used to monitor symptom severity over time [58].

Symptom severity assessment instrument — The Hospital Anxiety and Depression Scale is one of the most widely used instruments to assess and monitor the severity of symptoms of anxiety and depression. It is sensitive and specific in identifying pathological anxiety, has separate subscales for anxiety and depression, and includes questions that can distinguish symptoms of GAD from anxiety associated with other medical conditions [57].

The Penn State Worry Questionnaire is useful in assessing excessive worrying, has adequate psychometric properties, and is available in a number of languages but may be less sensitive to change than the GAD-7 [58].

DIAGNOSIS — The diagnosis of GAD is based on the presence of generalized, persistent and excessive anxiety and a combination of various psychological and somatic complaints.

Diagnostic criteria — The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria for GAD require the presence of [59]:

●A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least six months, about a number of events or activities (such as work or school performance).

●B. The individual finds it difficult to control the worry.

●C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past six months):

Note: Only one item is required in children.

•1. Restlessness or feeling keyed up or on edge

•2. Being easily fatigued

•3. Difficulty concentrating or mind going blank

•4. Irritability

•5. Muscle tension

•6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep)

●D. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

●E. The disturbance is not attributable to the physiological effects of a substance (eg, a drug of abuse, a medication) or another medical condition (eg, hyperthyroidism).

●F. The disturbance is not better explained by another mental disorder (eg, anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder [social phobia], contamination or other obsessions in obsessive-compulsive disorder (OCD), separation from attachment figures in separation anxiety disorder, reminders of traumatic events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physical complaints in somatic symptom disorder, perceived appearance flaws in body dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional beliefs in schizophrenia or delusional disorder). Because the majority of the anxiety symptoms are not specific to GAD, it is important to exclude the other anxiety disorders before making the diagnosis. (See "Social anxiety disorder in adults: Epidemiology, clinical manifestations, and diagnosis" and "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis" and "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis" and "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis" and "Specific phobia in adults: Epidemiology, clinical manifestations, course and diagnosis".)

The essential feature of diagnostic criteria for GAD in the World Health Organization’s ICD-10 is “free-floating” anxiety, with prominent tension, worry, and feelings of apprehension about everyday events and problems. Diagnosis additionally requires the presence of at least four more features from a list of 22 symptoms relating to autonomic arousal, tension, mental state, chest/abdominal discomfort, and sleep disturbance. Symptoms have to be present for most days over the preceding six months.

The diagnosis of GAD in children and adolescents is discussed further separately. (See "Anxiety disorders in children and adolescents: Epidemiology, pathogenesis, clinical manifestations, and course".)

Differential diagnosis

Depression — Primary GAD with secondary depressive symptoms can be difficult to distinguish from major depressive disorder or persistent depressive disorder (‘dysthymia’), as the conditions share many features such as an insidious onset, protracted course, prominent dysphoria and anxiety symptoms. Individuals with depression tend to brood self-critically on previous events and circumstances, whereas patients with GAD tend to worry about possible future events. Symptoms of depression such as early morning awakening, diurnal variation in mood, marked guilty preoccupations, and suicidal thoughts are all uncommon in GAD. (See "Unipolar depression in adults: Assessment and diagnosis".)

Hypochondriasis — Concern about medically unexplained symptoms is common to both GAD and hypochondriasis, but GAD is usually characterized by worries about multiple different things, while patients with hypochondriasis worry principally about illness.

Panic disorder — Panic attacks can occur in GAD, arising out of escalating and uncontrollable worry: but the presence of unexpected (uncued) panic attacks is unusual in GAD. Patients with panic disorder tend to have episodic and calamitous thoughts about presumed life-threatening acute illnesses, whereas patients with GAD focus more persistently on less specific but more chronic complaints involving multiple organ systems. (See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)

Adjustment disorder — Anxiety and other symptoms occur within three months of an identifiable stressor or stressors. Adjustment disorder is regarded as a “residual” category in which symptoms do not meet the criteria for another specific disorder.

Obsessive-compulsive disorder — Patients with GAD can show intrusive thoughts and checking behaviors with similarities to OCD. GAD themes tend to be more day to day worries (finances, work, health, family) while OCD tends to be about more primal fears (eg, contamination or harm). OCD compulsions are typically ritualistic/rule driven (has to be done a certain way) and either unrelated to the feared outcome they are intended to prevent (eg, avoiding cracks on side walk to prevent mother’s death) and/or clearly excessive; GAD checking is typically directly related to preventing the feared outcome (checking the locks on the front door before bedtime to prevent break-in) and is not usually excessive or time consuming. (See "Obsessive-compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".)

Separation anxiety disorder — The distinction between GAD and separation anxiety disorder largely rests on establishing that the fear and worry of losing loved ones is only one of a wide range of worrisome themes in patients with GAD, whereas in separation anxiety disorder, the central and often only concern is the fear of and worry about losing a major attachment figure.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anxiety and anxiety disorders in adults".)

SUMMARY AND RECOMMENDATIONS

●Generalized anxiety disorder (GAD) is characterized by excessive, pervasive, and persistent worrying which is difficult to control. The associated psychological and physical symptoms may cause significant personal distress and impairment of everyday functioning. (See 'Introduction' above.)

●GAD is common in community and clinical settings. It is likely the most common anxiety disorder in people aged over 65 years. Major depression and other anxiety disorders are common comorbidities of GAD. (See 'Comorbidity' above.)

●GAD is considered to be a chronic illness with fluctuating symptom severity. Comorbid GAD and major depression is more impairing and has a worse prognosis. (See 'Course' above and 'Comorbidity' above.)

●Genetic factors appear to predispose individuals to the development of GAD, though data from twin studies have been inconsistent. GAD shares a common heritability with major depression and with the personality trait of “neuroticism.” Adversity and undesirable life events can exacerbate symptoms of GAD. (See 'Biological factors' above.)

●Neuroimaging studies suggest that alterations in neurotransmitter response and glucose metabolism in fear-related brain circuits contribute to the development of GAD. In addition, cognitive, psychological, and developmental factors play a role. (See 'Pathogenesis' above.)

●Excessive and persistent worrying is the pathognomonic symptom of GAD, but symptoms related to hyperarousal, autonomic hyperactivity, motor tension, sleep disturbance, and pain are all common. (See 'Clinical manifestations' above.)

●Assessment of a patient with possible GAD should include a careful history, an evaluation for symptoms of GAD as well as alternative or comorbid psychiatric disorders. In addition, a physical examination and laboratory studies to rule out organic causes of anxiety should be done in cases with late onset anxiety, weight loss, cognitive impairment, or other findings suggestive of an underlying medical cause. (See 'Assessment' above.)

●The diagnosis of GAD is made in an individual with excessive anxiety and worry occurring more days than not for at least six months. The worry involves a number of events or activities (such as work or school performance) and is associated with three or more associated symptoms such as irritability, muscle tension, restlessness, or sleep disturbance. The anxiety worry or physical symptoms cause clinically significant distress or impairment in social, occupation, or other important areas of functioning. (See 'Diagnostic criteria' above.)

●Primary GAD with secondary depressive symptoms can be difficult to distinguish from major depressive disorder or persistent depressive disorder (‘dysthymia’), as the conditions share many features such as an insidious onset, protracted course, prominent dysphoria, and anxiety symptoms. Other diagnosis to consider in patients with presumed GAD include panic disorder, adjustment disorder, and hypochondriasis. (See 'Differential diagnosis' above.)