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Generalized anxiety disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment,

and diagnosis

Author Section Editor Deputy Editor

David Baldwin, DM FRCPsych Murray B Stein, MD, MPH Richard Hermann, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2013. | This topic last updated: Mar 28, 2013.

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 generalized anxiety disorder include psychological interventions such as cognitive-
behavioral therapy, and medications including selective serotonin reuptake inhibitors.

This topic addresses the epidemiology, pathogenesis, clinical manifestations, and diagnosis of generalized anxiety
disorder. Pharmacotherapy and psychotherapy for generalized anxiety disorder are discussed separately. (See
"Pharmacotherapy for generalized anxiety disorder" and "Psychotherapy for generalized anxiety disorder".)

EPIDEMIOLOGY — Generalized anxiety disorder (GAD) is common in both community and clinical settings.
Epidemiologic studies of nationally representative samples in the United States (US) have found a lifetime
prevalence of GAD of 5.1 percent [1,2] to 11.9 percent [3]. A review of epidemiological studies in Europe found a
12-month prevalence of 1.7 to 3.4 percent [4], and a lifetime prevalence of 4.3 to 5.9 percent [5].

GAD is one of the most common mental disorders in primary care settings and is associated with increased use of
health services [6]. In a study of adult primary care patients in four Nordic countries, the rates of GAD were 4.1 to
6.0 percent among men, and 3.7 to 7.1 percent among women [7].

The disorder is approximately twice as common in women as it is in men [1,3]. GAD is probably the most common
anxiety disorder among the elderly population [4,8].

Comorbidity — Comorbidity with major depression or other anxiety disorders has been observed in the majority of
cases of GAD [4]. In a nationally representative survey of US adults, 66 percent of individuals with current GAD
had at least one concurrent disorder [1]. Individual disorders found to co-occur in people with GAD (rates over the
previous 30 days and lifetime) included [1,9]:

Social phobia — 23.2 and 34.4 percent

Specific phobia — 24.5 and 35.1 percent
Panic disorder — 22.6 and 23.5 percent

GAD may also be associated with increased rates of substance abuse, posttraumatic stress disorder, and
obsessive-compulsive disorder. (See "Unipolar depression in adults: Epidemiology, pathogenesis, and
neurobiology" and "Social anxiety disorder: Epidemiology, clinical manifestations, and diagnosis" and "Specific
phobia in adults: Epidemiology, clinical manifestations, course and diagnosis" and "Panic disorder: Epidemiology,
pathogenesis, clinical manifestations, course, assessment, and diagnosis" and "Alcohol use disorder:
Epidemiology, pathogenesis, clinical manifestations, adverse consequences, and diagnosis" and "Posttraumatic
stress disorder: Epidemiology, pathophysiology, clinical manifestations, course, and diagnosis" and "Obsessive-
compulsive disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, and diagnosis".)

Patients with comorbid major depression and GAD tended to have a more severe and prolonged course of illness
and greater functional impairment [10]. The presence of comorbid major depressive episodes is associated with a

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poorer prognosis in patients with GAD. The NCS follow-up study found that patients with comorbid GAD and major
depression were significantly more likely to fulfil criteria for GAD ten years later [3].

GAD is common among patients with ‘medically unexplained’ chronic pain [11] and with chronic physical illness [12].
(See 'Course' below.).

PATHOGENESIS

Biological factors — Genetic factors appear to predispose individuals to the development of generalized anxiety
disorder (GAD), though data from twin studies have been inconsistent. GAD shares a common heritability with
major depression [13] and with the personality trait of “neuroticism” [14,15]. The serotonin transporter gene-linked
polymorphic region SS genotype (short/short) has been found to be more frequent in patients with GAD [16].
Variations in two sub-types of the glutamic acid decarboxylase gene may increase individual susceptibility to
anxiety disorders, including GAD [17,18].

Investigations of potential disturbances in the principal neurotransmitters norepinephrine, 5-hydroxtryptamine (5-HT,

serotonin) and gamma aminobutyric acid (GABA) in GAD have tended to be small, inconsistent, or unreplicated.
Early studies suggested the levels of the norepinephrine metabolites 3-methoxy-4-hydroxyphenylgycol and
vanillylmandelic acid are increased in patients with GAD [19,20]. The growth hormone response to clonidine
challenge has been found to be blunted, suggesting decreased postsynaptic alpha-2 adrenergic receptor sensitivity
[21]. Elevated urinary levels of the serotonin metabolite 5-hydroxyindoleacetic acid are associated with greater
anxiety severity [20]. Benzodiazepine binding sites on platelets and lymphocytes are reduced in density in patients
with GAD, but increase in density after administration of diazepam [22,23].

Neuropsychological factors — A study of positron emission tomography (PET) 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 [24]. A functional MRI
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 [25].

Investigations of the processing of emotional information suggest that GAD may be associated with specific biases
for mood-congruent information [26]. Patients with GAD have been found to allocate extensive attentional
resources to threatening stimuli, detect ‘threats’ rapidly and effectively [27], and misinterpret ambiguous information
as being threatening [28]. These biases diminished with successful treatment with cognitive-behavioral therapy [29]
or a selective serotonin reuptake inhibitor [30].

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 [31].
GAD is more likely to occur in people with ‘behavioral inhibition’, which is the tendency to be timid and shy in novel
situations [32]. The personality trait of ‘neuroticism’ (or negative affectivity) is associated with comorbid GAD and
major depression [33,34].

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 [35]

Develop worrying in an attempt to solve problems [36]
Use worrying to avoid the fear response [37]
Have intolerance of uncertainty or ambiguity [38]
Worry about the uncontrollability and presumed dangerous consequences of worrying [39].

CLINICAL MANIFESTATIONS — Although excessive and persistent worrying is widely regarded as the
pathognomic feature of generalized anxiety disorder (GAD), most patients present with other symptoms relating to
hyperarousal, autonomic hyperactivity and motor tension. Many 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

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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 non-anxious controls [40]. Individuals with GAD have been
distinguished from controls, and from patients with other anxiety disorders, by having greater worry over minor
matters [40]. Patients with GAD typically respond positively to the question, “Do you worry excessively about minor
matters?”, while a negative response effectively rules out the diagnosis of GAD [41].

COURSE — Generalized anxiety disorder (GAD) is considered to be a potentially chronic illness, fluctuating in
symptom severity over time. Longitudinal studies in treatment-seeking patients generally provide evidence for a
prolonged and fluctuating course of illness. A prospective study of 179 patients with generalized anxiety disorder
(DSM-III-R) in the US found that approximately 60 percent of patients recovered over 12 years (ie, had no more
than residual symptoms for eight consecutive weeks), but around one-half of recovered patients subsequently
relapsed during the 12 year period [42] The decline in mean anxiety symptom severity in the patients with GAD
was only modest [43].

Studies of people with GAD in community samples suggest a better prognosis than studies of clinical populations.
A 22-year follow up study of 105 individuals meeting 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) [44].

GAD typically has a gradual evolution [45] and an onset of the full syndromal disorder that is later than that seen
with some other anxiety disorders, though sub-syndromal anxiety symptoms are common before the age of 20
years [44]. Patients with an early age of onset tend to have a more protracted course and present with comorbid
depression or other disorders [46]. Late-onset GAD usually starts abruptly, and is associated with clearly
identifiable stressors.

GAD is associated with a significant degree of functional impairment, similar to that with major depression [47,48].

GAD and, in particular, worrying have been associated with poor cardiovascular health and with coronary heart
disease [49] 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

ASSESSMENT — Psychiatric assessment of a patient with possible generalized anxiety disorder (GAD) should
include a careful history and evaluation for symptoms of GAD and other psychiatric disorders. (See 'Differential
diagnosis' below and 'Comorbidity' above.)

Patients who have findings suggesting a possible physical cause of anxiety symptoms — for example, patients with
late-onset anxiety, with weight loss, or with cognitive impairment — should receive a physical exam and laboratory
studies consistent with physical findings (eg, complete blood count, chemistry panel, serum thyrotropin (TSH),
urinalysis, electrocardiogram [in patients over 40 with chest pain or palpitations], or urine or serum toxicology
analysis for drugs or medications).

Other components of a psychiatric evaluation that should be emphasized include:

A substance abuse history that includes alcohol, prescription drugs, caffeine, and nicotine

A medical history that focuses on possible contributory factors relating to current medical disorders or
medication side effects

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A family psychiatric history

A social history that screens for stressful life events and past sexual, physical and emotional abuse, or
emotional neglect

Screening instrument — The generalized anxiety disorder seven-item (GAD-7) scale 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 [50]. The GAD-7 has been found to be sensitive to change and can be used to monitor symptom
severity over time (table 1) [51].

Symptom severity assessment instrument — The Hospital Anxiety and Depression Scale (HADS) 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
[52].

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 [53].

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

DSM-IV-TR diagnostic criteria for generalized anxiety disorder require [54]:

Excessive anxiety and worry, occurring more days than not for at least six months, about a number of
events or activities

The person finds it difficult to control the worry.

The anxiety and worry are associated with at least three of the following symptoms

Restlessness
Being easily fatigued
Difficulty concentrating
Irritability
Muscle tension
Sleep disturbance

The focus of the anxiety and worry is not confined to features of another Axis I disorder, eg, the anxiety or
worry is not about having a panic attack, as in panic disorder

The anxiety, worry, or physical symptoms cause clinically significant distress or impaired functioning.

The disturbance is not due to the direct physiological effects of a substance or a general medical condition

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: Epidemiology, clinical manifestations, and
diagnosis" and "Panic disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and
diagnosis" and "Posttraumatic stress disorder: Epidemiology, pathophysiology, clinical manifestations, course, 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.

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The diagnosis of GAD in children and adolescents is described separately.

The diagnosis of GAD in elderly individuals can be challenging due to the common co-occurrence of long-term
physical illnesses, chronic insomnia, cognitive impairment, and the side effects of prescribed medication. Elderly
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?”

Differential diagnosis

Depression — Primary GAD with secondary depressive symptoms can be difficult to distinguish from major
depression or 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, and suicidal thoughts are all uncommon in
GAD.

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.

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.

SUMMARY AND RECOMMENDATIONS

Generalized anxiety disorder (GAD) is characterized by excessive, persistent worrying which is hard to
control, and by psychological and physical symptoms of anxiety that together cause significant personal
distress and impairment of everyday functioning. (See 'Introduction' above.)

GAD is common in community and clinical settings. It is probably the most common anxiety disorder in
people aged over 65 years. Major depression and other anxiety disorders are common comorbidities of
GAD. (See 'Epidemiology' 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. Neuroimaging
and other studies suggest the symptoms of GAD are accompanied by an enhanced emotional
responsiveness in fear-related brain circuits. (See 'Pathogenesis' above.)

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

GAD tends to run either a chronic course fluctuating in severity over time, or an episodic course with some
intervening periods of relative well-being. Comorbid GAD and major depression is more impairing and has a
worse prognosis. (See 'Course' 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, and a physical exam and laboratory studies to
rule out organic causes of anxiety. (See 'Assessment' above.)

Distinguishing GAD from major depression and dysthymia is probably the most difficult part of the disorder’s

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differential diagnosis, as the conditions share 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.
(See 'Differential diagnosis' above.)

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GRAPHICS

GAD-7 anxiety scale

Over the last 2 weeks, how often have you been bothered by the
following problems?

More than
Several Nearly
Not at all half the
days every day
days

1. Feeling nervous, anxious or on 0 1 2 3

edge

2. Not being able to stop or control 0 1 2 3

worrying

3. Worrying too much about different 0 1 2 3

things

4. Trouble relaxing 0 1 2 3

5. Being so restless that it is hard to 0 1 2 3

sit still

6. Becoming easily annoyed or 0 1 2 3

irritable

7. Feeling afraid as if something awful 0 1 2 3

might happen

Total score* _____ = Add _____ + _____ + _____

Columns

If you checked off any problems, how difficult have these problems made it for you to do your
work, take care of things at home, or get along with other people?

Circle one Not difficult Somewhat Very difficult Extremely

at all difficult difficult

* Score: 5-9 = mild anxiety; 10-14 = moderate anxiety; 15-21 = severe anxiety.
Adapted and reproduced with permission from: Spitzer RL, Kroenke K, Williams JB, Lowe B. A brief measure
for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006; 166:1092. Copyright © 2006
American Medical Association.

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