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Generalized anxiety disorder: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis Author David Baldwin, DM FRCPsych 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 cognitivebehavioral 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 "Obsessivecompulsive 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 1 de 7 02/12/2013 05:04 Section Editor Murray B Stein, MD, MPH Deputy Editor Richard Hermann, MD

Generalized anxiety disorder: Epidemiology, pathogenesis, clinical man...

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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 Organizations 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 disorders

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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.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 496 Version 9.0

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GRAPHICS GAD-7 anxiety scale

Over the last 2 weeks, how often have you been bothered by the following problems?
Not at all 1. Feeling nervous, anxious or on edge 2. Not being able to stop or control worrying 3. Worrying too much about different things 4. Trouble relaxing 5. Being so restless that it is hard to sit still 6. Becoming easily annoyed or irritable 7. Feeling afraid as if something awful might happen Total score* _____ = 0 0 0 0 0 0 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 at all Somewhat difficult Very difficult Extremely difficult 1 1 1 1 1 1 _____ + 2 2 2 2 2 2 _____ + 3 3 3 3 3 3 _____ 0 1 Several days 2 More than half the days Nearly every day 3

* 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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