Generalized Anxiety Disorder

Etiology

The etiology of generalized anxiety disorder may include:

• Stress
• Medical conditions, such as diabetes
• Comorbid mental health conditions, such as depression
• Genetic factors, with generalized anxiety disorder occurring in approximately 25% of first-degree relatives of affected patients
• Environmental factors, such as childhood abuse
• Substance use disorder

Epidemiology

Childhood anxiety occurs in about 1 in 4 adolescents at some time between the ages of 13 and 18 years. The median age of onset is 11 years. However, the lifetime prevalence of severe anxiety disorders among adolescents aged 13 to 18 years is approximately 6%. The overall prevalence among individuals younger than 18 years ranges from 5.7% to 12.8%. The prevalence is approximately twice as high among women as among men.[4][5][6]

The American Psychiatric Association first introduced the diagnosis of generalized anxiety disorder in the DSM-III. Previously, clinicians conceptualized generalized anxiety disorder as 1 of the 2 core components of anxiety neurosis, with panic representing the other component. Recognition that generalized anxiety disorder and panic, although often occurring together, were sufficiently distinct to be considered independent disorders led to their separation in the DSM-III.

The DSM-III definition of generalized anxiety disorder required uncontrollable and diffuse anxiety or worry that was not focused on a single major life problem, was excessive or unrealistic relative to objective life circumstances, and persisted for 1 month or longer. Several related psychophysiological symptoms were also required for the diagnosis. Results from early clinical studies evaluating the DSM-III criteria found that the disorder seldom occurred in the absence of a comorbid anxiety or mood disorder. The comorbidity between generalized anxiety disorder and major depressive disorder was especially strong. Consequently, some commentators suggested that generalized anxiety disorder might be better conceptualized as a prodrome, residual condition, or marker of severity rather than as an independent disorder. The rate of comorbidity between generalized anxiety disorder and other disorders decreased with longer durations of generalized anxiety disorder. Based on these findings, the DSM-III-R committee on generalized anxiety disorder recommended increasing the required duration to 6 months. The final version of the DSM-III-R incorporated this change. The DSM-IV subsequently revised the definition of excessive worry and the required number of associated psychophysiological symptoms.

Changes in diagnostic criteria delayed the accumulation of epidemiological data on generalized anxiety disorder. Nonetheless, relevant epidemiological evidence emerged during the subsequent decade. As discussed later, these findings challenged the view that generalized anxiety disorder should be conceptualized as a prodrome, residual condition, or marker of the severity of other disorders. Instead, results from epidemiological studies suggested that generalized anxiety disorder is a common disorder that, although often comorbid with other mental disorders, does not have a higher comorbidity rate than the rates observed with most other anxiety or mood disorders. The findings also raised questions about the validity of the diagnostic thresholds established in the DSM-5.

Pathophysiology

The exact mechanism underlying generalized anxiety disorder remains unclear. Anxiety can be a normal phenomenon in children. Stranger anxiety begins at age 7 to 9 months. Noradrenergic, serotonergic, and other neurotransmitter systems appear to play a role in the body's response to stress. The serotonin and noradrenergic systems are common pathways involved in anxiety. Reduced serotonergic activity and increased noradrenergic activity may contribute to the development of generalized anxiety disorder. Consequently, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications for treatment.

History and Physical

Patients with anxiety can pose a diagnostic challenge because somatic symptoms are more common than psychological symptoms. Most patients present with vague or nonspecific somatic concerns, including shortness of breath, palpitations, fatigue, headache, dizziness, and restlessness. Patients may also describe psychological symptoms, such as excessive nonspecific anxiety and worry, emotional lability, difficulty concentrating, and insomnia.

Factors commonly associated with generalized anxiety include:

• Female sex
• Unmarried
• Poor health
• Low education
• Presence of stressors

The median age at presentation is 30 years. Numerous scales have been developed to assess symptom severity and support diagnosis. The Generalized Anxiety Disorder 7-item scale (GAD-7) has been validated as a diagnostic and severity assessment tool.

Evaluation

Initial assessment begins with evaluation of behavioral or somatic symptoms. Clinicians should evaluate patients for psychosocial stress, psychosocial difficulties, and developmental concerns. The medical history should include previous trauma, psychiatric conditions, and substance use disorder.[7]

The following tests may be obtained to exclude medical causes:

• Thyroid function tests
• Blood glucose level 
• Echocardiography
• Toxicology screen

The Generalized Anxiety Disorder 7-Item (GAD-7) questionnaire is a screening tool that can also be used to monitor patients with generalized anxiety disorder.

Treatment / Management

The 2 main treatments for generalized anxiety disorder are cognitive behavioral therapy and medications. Patients may benefit most from a combination of the 2. Determining the most effective treatment may require several therapeutic trials.[8][9][10](A1)

Cognitive Behavioral Therapy

Cognitive behavioral therapy includes psychoeducation, modification of maladaptive thought patterns, and gradual exposure to anxiety-provoking situations.

Pharmacotherapy

Patients who do not respond to cognitive behavioral therapy may be treated with medication. Some patients with severe symptoms may initially receive cognitive behavioral therapy and medication concurrently. Several types of medications are used to treat generalized anxiety disorder.

Antidepressants

First-line medications include selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which have response rates ranging from 30% to 50%. Medications in these classes include escitalopram, duloxetine, venlafaxine extended-release, and paroxetine. Results from a study showed that 81% of children with anxiety disorders who received combined sertraline hydrochloride and cognitive behavioral therapy responded to treatment.

Antipsychotics

Antipsychotic medications may benefit some patients, particularly those with associated behavioral symptoms.

Benzodiazepines

Long-acting benzodiazepines include diazepam and clonazepam. These agents are used when an immediate reduction in symptoms is desired or when short-term treatment is needed. Patients who understand the psychological basis of their symptoms and can use the medication as prescribed may be more likely to respond to benzodiazepines. Because of the potential for misuse and dependence, benzodiazepines may be inappropriate for patients with a history of alcohol or other substance use disorder.

Buspirone 

Buspirone is a nonbenzodiazepine anxiolytic that does not cause dependence, causes less sedation than benzodiazepines, and does not lead to tolerance at therapeutic doses. However, its therapeutic onset of 2 to 3 weeks limits its usefulness when rapid symptom relief is needed. Pharmacotherapy requires gradual dose titration and continuation for at least 4 weeks to assess effectiveness. Once symptoms are controlled, treatment should continue for at least 12 months, followed by gradual tapering.

Ongoing monitoring is essential because adverse effects, including weight gain, hyperlipidemia, and diabetes, may occur with some medications. Psychotherapy is an effective adjunct to pharmacologic treatment, and patient education helps patients identify and manage anxiety triggers. Recommended strategies include limiting caffeine, alcohol, nicotine, and stress while improving sleep.

Although many complementary and alternative treatments are available, evidence supporting their benefit is limited, and some options carry risks. Kava may cause liver injury, whereas St John’s wort and 5-hydroxytryptophan may interact with SSRIs and precipitate serotonin syndrome.

Differential Diagnosis

The differential diagnoses for generalized anxiety disorder include the following:

• Hyperthyroidism
• Pheochromocytoma
• Chronic obstructive pulmonary disease
• Transient ischemic attack
• Epilepsy
• Bipolar disorder
• Use of caffeine, decongestants, and albuterol

Prognosis

The prognosis for patients with generalized anxiety disorder is guarded. Many patients have difficulty adhering to prescribed medications because of cost and adverse effects. Relapses are common, and patients often seek clinicians who can better address their needs. Because conventional treatments do not cure the disorder, many patients pursue alternative therapies, often without substantial benefit. Overall, generalized anxiety disorder may substantially impair patients’ quality of life.

Complications

Complications of generalized anxiety disorder can also lead to, or worsen, other mental and physical conditions, including:

• Depression (often presents concomitantly with an anxiety disorder) 
• Insomnia
• Drug or alcohol use disorder
• Gastrointestinal tract problems
• Social isolation
• Issues functioning at work or school
• Impaired quality of life
• Suicide potential [11]