Generalized Anxiety Disorder

Etiology

The etiology of generalized anxiety disorder may include:

• Stress
• A physical condition such as diabetes or other comorbidities such as depression
• Genetic, first-degree relatives with generalized anxiety disorder (25%)
• Environmental factors, such as child abuse
• Substance use disorder

Epidemiology

Childhood anxiety occurs in about 1 in 4 children at some time between the ages of 13 and 18 years. The median age at onset is 11 years. However, the lifetime prevalence of a severe anxiety disorder in children ages 13 to 18 is approximately 6%. The general prevalence in children under 18 years is between 5.7% and 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 2 decades ago in the DSM-III. Before that time, generalized anxiety disorder was conceptualized as 1 of the 2 core components of anxiety neurosis, the other being panic. A recognition that generalized anxiety disorder and panic, although often occurring together, are sufficiently distinct to be considered independent disorders led to their separation in the DSM-III.

The DSM-III definition of a generalized anxiety disorder requires uncontrollable and diffuse (ie, not focused on a single major life problem) anxiety or worry that is excessive or unrealistic relative to objective life circumstances and persists for one month or longer. Several related psychophysiological symptoms were also required for a diagnosis of generalized anxiety disorder. Early clinical studies evaluating DSM-III, according to this definition, found that the disorder seldom occurred in the absence of another comorbid anxiety or mood disorder. The comorbidity of generalized anxiety disorder and major depression was especially strong. It led some commentators to suggest that generalized anxiety disorder might better be conceptualized as a prodrome, residual, or severity marker than as an independent disorder. The rate of comorbidity of generalized anxiety disorder with other disorders decreases as the duration of generalized anxiety disorder increases. Based on this finding, the DSM-III-R committee on generalized anxiety disorder recommended that the duration required for the disorder be increased to 6 months. This change was implemented in the final version of the DSM-III-R. Additional changes in the definition of excessive worry and the required number of associated psychophysiological symptoms were made in the DSM-IV.

These changes in diagnostic criteria led to delays in cumulating data on the epidemiology of generalized anxiety disorder. Nonetheless, such data became available over the past decade. As described in more detail later, this new data challenged the view that generalized anxiety disorder should be conceptualized as a prodrome, residual, or severity marker of other disorders. Instead, it suggests that generalized anxiety disorder is a common disorder that, although often comorbid with other mental disorders, does not have a higher comorbidity rate than those found in most other anxiety or mood disorders. The new data also challenged the validity of the threshold decisions embodied in the DSM-5.

Pathophysiology

The exact mechanism is not entirely known. Anxiety can be a normal phenomenon in children. Stranger anxiety begins at 7 to 9 months of life. Noradrenergic, serotonergic, and other neurotransmitter systems appear to play a role in the body's response to stress. The serotonin system and the noradrenergic systems are common pathways involved in anxiety. Many believe that low serotonin system activity and elevated noradrenergic system activity are responsible for its development. Therefore, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are the first-line agents for its treatment. 

History and Physical

Patients with anxiety can pose a diagnostic challenge, as somatic symptoms are more common than psychological symptoms. Most patients present with vague or nonspecific somatic complaints, including, but not limited to, shortness of breath, palpitations, fatigability, headache, dizziness, and restlessness. Patients may also describe psychologic symptoms such as excessive, nonspecific anxiety and worry, emotional lability, difficulty concentrating, and insomnia.

Factors commonly associated with generalized anxiety include:

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

The median age of presentation is 30 years. Many scales have been developed to assess the severity and diagnosis. The GAD-7 has been validated as a diagnostic tool and severity assessment scale.

Evaluation

Initial assessment begins by addressing behavioral or somatic symptoms. Evaluate for psychosocial stress, psychosocial difficulties, and developmental issues. Review past medical history, including trauma, psychiatric conditions, and substance abuse.[7]

The following evaluation may be obtained to exclude organic 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 two. It may take some trial and error to discover which treatments work best.[8][9][10](A1)

Cognitive Behavioral Therapy

This includes psychoeducation, changing maladaptive thought patterns, and gradual exposure to anxiety-provoking situations.

Pharmacotherapy

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

Antidepressants

The first-line agents are SSRI and SNRI classes, with a response rate of 30% to 50%. This class of drugs includes escitalopram (Lexapro), duloxetine (Cymbalta), venlafaxine (Effexor XR), and paroxetine (Paxil, Pexeva). In a study, 81% of children with anxiety disorders who received combined sertraline hydrochloride and cognitive behavioral therapy responded to the treatment.

Antipsychotics

These may also help some patients, especially those with associated behavior problems.

Benzodiazepines

Examples are diazepam and clonazepam, which are long-acting agents. These agents are used when an immediate reduction of symptoms is desired or a short-term treatment is needed. Generally, cooperative and compliant patients who are aware that their symptoms have a psychological basis are more likely to respond to benzodiazepines. Since there is a concern for misuse and dependence, patients with a history of alcoholism or drug abuse are not appropriate candidates for this treatment.

Buspirone 

Buspirone is a nonbenzodiazepine that does not cause dependency. It is also less sedating than benzodiazepines, and tolerance does not occur at therapeutic doses. This agent has a therapeutic lag in the efficacy of 2 to 3 weeks, limiting its use.

All medications should be titrated slowly and continued for at least 4 weeks to determine if they work. Once symptoms are under control, the medications must be used for at least 12 months before gradually tapering them. Every medication has adverse effects, such as weight gain, hyperlipidemia, and diabetes; thus, the patients need to be monitored.

Psychotherapy is used in addition to medications; this combination has proven to be effective.

The education of the patient is vital as it can help ease anxiety. The triggers for anxiety should be managed by avoiding caffeine, alcohol, nicotine, and stress) and improving sleep.

Many complementary and alternative remedies are available, but the evidence to support their efficacy is lacking. Further, some agents like Kava may injure the liver. Others, like St John's wort and hydroxytryptophan, may interact with SSRIs and induce 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 are not compliant with medications because of cost and adverse effects. Relapses are common, and patients often search for physicians who comply with their needs. Because of the lack of conventional medicine to cure the disorder, many opt for alternative therapies without much success. Overall, the quality of life of these patients is poor.

Complications

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

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