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Generalized Anxiety Disorder
Generalized Anxiety Disorder
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2022. | This topic last updated: Apr 18, 2022.
INTRODUCTION
Generalized anxiety disorder (GAD) is characterized by excessive and persistent worry that is
difficult to control, causes significant distress or impairment, and occurs on more days than
not for at least six months. Other features include psychological symptoms such as
apprehension and irritability, and physical (or somatic) symptoms such as increased fatigue
and muscular tension.
This topic addresses the epidemiology, pathogenesis, clinical manifestations, and diagnosis of
GAD. Pharmacotherapy for GAD, psychotherapy for GAD, and issues concerning treatment
and assessment of comorbid disorders are discussed separately:
EPIDEMIOLOGY
Epidemiologic studies of nationally representative samples in the United States report a past-
year prevalence of GAD to be 2.7 to 3.1 percent [3,4] and a lifetime prevalence of GAD of 5.1
[2,5] to 11.9 percent [6]. A review of epidemiological studies in Europe found a past-year
prevalence of 1.7 to 3.4 percent [7], and a lifetime prevalence of 4.3 to 5.9 percent [8].
Worldwide, estimates of the lifetime and 12-month prevalence are 3.7 and 1.8 percent,
respectively [9].
Major depressive disorder appears to be the most common comorbidity in individuals with
current or lifetime GAD. Comorbid major depression is reported in 39 percent of individuals
with current GAD and 62 percent of individuals with lifetime GAD [2,7]. Worldwide, mood
disorders have an estimated lifetime comorbidity of 63 percent [9].
Other disorders found to co-occur in individuals with GAD (rates over previous 30 days and
lifetime) include [2,13]:
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
● 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 alcohol and other substance use
disorders, posttraumatic stress disorder, and obsessive-compulsive disorder.
GAD is common among patients with “medically unexplained” chronic pain [14] and with
chronic physical illness [15].
PATHOGENESIS
Biological factors
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
Other data suggests the role of acid-sensing ion channels in the amygdala [28] and
elevated levels of C reactive protein and other proinflammatory cytokines [29] as
potentially involved in the development of GAD.
Additionally, alterations in glucose metabolism in the cortex, limbic system, and basal
ganglia suggest their role in the development of anxiety. For example, in one study,
positron emission tomography (PET) of 18 individuals with GAD were compared with PET
of 15 individuals without GAD (control group) [31]. PET scans of individuals 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
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
In a separate functional MRI study, individuals with GAD showed greater anticipatory
activity in the bilateral dorsal amygdala to both aversive and neutral pictures [32]. This
suggests an enhanced anticipatory emotional responsiveness in GAD [31,32]. A
systematic review of neuroimaging studies found that GAD patients show difficulties in
engaging the prefrontal cortex and anterior cingulate cortex during emotional
regulation tasks [33].
GAD is more likely to occur in individuals with “behavioral inhibition” (the tendency to be
timid and shy in novel situations), than without this trait. Additionally, neuroticism (an
enduring tendency to worry and feel anxious, sad, or guilty) is associated with comorbid
GAD and major depression [42-44]. (See "Social anxiety disorder in adults: Epidemiology,
clinical manifestations, and diagnosis", section on 'Behavioral inhibition'.)
● Cognitive origins of worry – Many explanations of the origin and persistence of the
excessive and pervasive worrying that characterize GAD have been proposed. As
examples, affected individuals may:
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
Onset — The average age of onset of GAD is 30 years, although the range is broad [50]. While
subsyndromal anxiety symptoms are common before the age of 20, full syndromal disorder
typically occurs later than other anxiety disorders (eg, separation anxiety disorder, phobias,
panic disorder) [51,52].
Studies examining the effect of age of onset on the course of GAD have shown mixed results.
While some studies have suggested that earlier age of onset is associated with a more
protracted course [53], others find that early-onset GAD does not constitute a more severe
subtype [54].
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
Individuals with late-onset GAD are more likely to a report a poorer health-related
quality of life than individuals with earlier onset GAD [55-57].
In a community survey including 1974 adults age ≥65 years, nearly 25 percent reported
a late onset of generalized anxiety symptoms [58]. Factors associated with late-onset
GAD include female sex, chronic physical illness (eg, respiratory, cardiovascular,
cognitive), current major depression or phobia, recent adverse life events, negative
childhood events (eg, parental loss or separation, parental mental health problems),
financial difficulties, and past history of GAD [56,59].
In one prospective study of 179 individuals with GAD, 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 [60].
In another prospective study involving 142 subjects with GAD followed for 14 years, the
severity of anxiety symptoms over time decreased only modestly [61].
Effects of illness
For example, in a national epidemiologic survey of adult mental health in Germany (n = 4181),
the impact of psychiatric symptoms on daily functioning and perceived quality of life was
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
assessed [64]. A greater percentage of respondents with the diagnosis of GAD reported six or
more days with impairment (defined as inability to work or carry out everyday activities) over
the past month than respondents with major depression or no diagnosis (34 versus 21 versus
2 percent respectively). Furthermore, lower scores on measures of quality of life including
general health and mental health (as measured on the 100-point Medical Outcomes Study
Short Form-36) were seen in individuals with GAD versus major depression versus no
diagnosis (general health: 47 versus 59 versus 68 respectively; mental health: 34 versus 42
versus 51, respectively).
The presence of comorbid disorders such as major depression appear to be associated with
more severe and prolonged course of illness and greater functional impairment [6,12,60]. For
example, in a national survey, a greater percentage of individuals with both GAD and major
depression reported six or more days of impairment in the past month than individuals with
either GAD or major depression (48 versus 34 versus 21 percent respectively) [64].
Additionally, the survey showed that a greater percentage of individuals with both disorders
had over 50 percent reduction in overall activities than individuals with generalized anxiety or
major depression (23 versus 11 versus 8 percent respectively). (See 'Comorbidity' above.)
Prospective studies suggest that clinically significant anxiety in the midlife period may be an
independent risk factor for the development of dementia [67].
Assessment
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
● First, we assess the frequency, character, and severity of symptoms to raise or lower
suspicion for the diagnosis of GAD by asking the following questions. Using a symptom
scale, such as the GAD seven-item (GAD-7) scale (calculator 1), can also be helpful to try
to quantify the severity of symptoms (see 'Quantifying the severity of symptoms' below):
• Does the anxiety concern every day or routine circumstances or events (eg, job
responsibility, health of self or family members, finances, misfortunes, or other
minor tasks such as household chores)?
• Have the symptoms been present for more than six months?
In individuals who answer yes to all of the above questions we further consider the
diagnosis of GAD and rule out other diagnoses that present with similar or overlapping
syndromes and other comorbid diseases. (See 'Diagnostic criteria' below and
'Differential diagnosis' below.)
Individuals who answer no to any of these questions probably do not meet the
American Psychiatric Association’s Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5) criteria for GAD.
● For people who would meet DSM-5 criteria for GAD or have a likely diagnosis of GAD
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
based on the severity and frequency of symptoms as above, we review prior psychiatric
history and rule out other psychiatric diagnoses as potential causes of anxiety. We do
this by establishing the presence or absence of symptoms that may differentiate
between disorders:
• Rapid onset and resolution of symptoms – Symptoms that start rapidly, sharply rise
in intensity, peak within an hour, and then decline are suggestive of discrete anxiety
attacks which suggests panic disorder rather than GAD.
These and other psychiatric disorders that can share symptomatology with GAD are
discussed in further detail elsewhere. It is also possible for these disorders to coexist
with GAD. (See 'Differential diagnosis' below.)
● We ask about physical health problems (eg, thyroid disease, asthma) and their effects.
We review the individual’s use of prescribed medications (eg, steroids, bronchodilators)
as these may be causing or worsening the anxiety. We also ask about alcohol and other
substance use or recent abstinence from alcohol or other substances.
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
shortness of breath) and in individuals with later onset of generalized anxiety (eg, older than
50 years) we do a general physical screening examination and laboratory testing to screen for
underlying medical disorders. We typically obtain a complete blood count, chemistry panel,
serum thyrotropin, urinalysis, electrocardiogram (in patients over 40 with chest pain or
palpitations), and urine toxicology. In cases with suspected underlying medical cause, we
refer to the appropriate specialist for further evaluation.
Quantifying the severity of symptoms — In all individuals with symptoms suspicious for
GAD, we use the GAD-7 scale (calculator 1) as a means of measuring the level of anxiety.
Additionally, in individuals with confirmed GAD we use the GAD-7 periodically, to monitor
symptoms and judge the response to treatment. The GAD-7 has acceptable reliability and
validity [68] and is sensitive to change in symptoms [69].
The Penn State Worry Questionnaire is available in a number of languages but does not
assess all key symptoms and may be less sensitive to change than the GAD-7 [69].
For hospitalized individuals with active medical disorders, we use the Hospital Anxiety and
Depression Scale to assess and monitor the severity of anxiety and depression. It is useful 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 [68].
Diagnostic criteria — We diagnose GAD in individuals with excessive anxiety and worry that
occur on more days than not for at least six months, are associated with somatic symptoms
(muscle tension, irritability, sleep disturbance), are not due to effects of substances or
another medical condition, and cause clinically significant distress or impairment in social,
occupation, or other important areas of functioning. In patients who “fall short” of the
severity or duration thresholds, further review is advisable, particularly in those who are
significantly distressed or impaired in functioning.
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
● 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).
● 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):
• 4. Irritability
• 5. Muscle tension
● 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 OCD, separation from
attachment figures in separation anxiety disorder, reminders of traumatic events in
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
The essential feature of diagnostic criteria for GAD in the World Health Organization
International Classification of Diseases, 11th revision (ICD-11) is generalized apprehension or
excessive worry, together with additional symptoms such as muscular tension, subjective
experience of nervousness, difficulty maintaining concentration, irritability, or sleep
disturbance. Symptoms have to be present for most days over the preceding several 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".)
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
prominent dysphoria, and anxiety. We differentiate individuals with primary GAD from
those with other depressive disorders by the characteristics of the worry and the
presence or absence of associated symptoms. For example, individuals with depression
tend to brood self-critically about previous events and circumstances, whereas patients
with GAD tend to worry about future events. Furthermore, symptoms such as early
morning awakening, diurnal variation in mood, marked guilty preoccupations, and
suicidal thoughts may be present in depression but are uncommon in GAD. (See
"Unipolar depression in adults: Assessment and diagnosis".)
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
months of the symptoms in adjustment disorder. In GAD, the symptoms are chronic and
while they may be related to chronic stressors of life, when they are within three months
of an acute stressor, the diagnosis of adjustment disorder is made.
Links to society and government-sponsored guidelines from selected countries and regions
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
around the world are provided separately. (See "Society guideline links: Anxiety and anxiety
disorders in adults".)
● Clinical manifestations – Individuals with GAD experience worry about typical life
experiences such as work, health, and interpersonal relations. The symptoms are out of
proportion to the impact of the anticipated event. Other presenting symptoms
commonly include hyperarousal, autonomic hyperactivity, irritability, poor sleep, and
unexplained pain or muscle tension.
● Course – GAD usually has a gradual onset with subsyndromal anxiety commonly
presenting before age 20. The average onset of the disorder is 30. Late-onset GAD (eg,
≥50 years) is common and is associated with poor health-related quality of life. (See
'Onset' above.)
GAD is associated with poor cardiovascular health, coronary heart disease, and
cardiovascular mortality. (See 'Systemic effects' above.)
● Assessment – For patients who present with anxiety, we assess whether the frequency,
character, and severity of symptoms are consistent with GAD. We also evaluate for other
alternative or comorbid psychiatric and medical conditions that may also contribute to
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
anxiety. In individuals with a suspected physical cause of anxiety (eg, weight loss,
confusion) and in individuals with later onset (>50 years old) of generalized anxiety, we
do a general physical screening examination and laboratory screening. (See
'Assessment' above.)
● Differential diagnosis – We differentiate anxiety due to GAD from other disorders that
may present with overlapping symptoms (eg, depression, panic disorder, adjustment
disorder) primarily by history. Major depression is particularly difficult to distinguish
from GAD due to shared symptoms of insidious onset, protracted course, and the
presence of dysphoria and anxiety. (See 'Differential diagnosis' above.)
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Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis
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