Generalized Anxiety Disorder

An essential feature of generalized anxiety disorder (GAD) is unrealistic or excessive worry and apprehension about life circumstances. Sources of such worry can be varied but are often commonplace issues including health, finances, social acceptance, employment and job performance, family and marriage.

This disorder may seem like a simple exaggeration of everyday concerns, but it is overshadowed by more severe tension, intrusive worries, anxious mood, and other symptoms. Comorbidity is common, and patients may suffer as “chronic worriers” without treatment.

To meet DSM-5 criteria, the anxiety and worry should be present for at least 6 months, and the person should have difficulty controlling the worry.

The symptoms involved with GAD are both psychological and physical.

Psychologically, the person with GAD can experience apprehension, anxiety, and hypervigilance. The latter reflects a propensity to mentally scan the environment to anticipate future stressors.

In other words, the negative anticipation of the “next bad thing” is continually present.

As well, people with GAD may startle easily and find themselves irritable and impatient. They often ruminate about potential unfortunate events such as the death of a family member, financial disaster, social rejection, serious illness, or job termination. Even though the person may understand that the fears are unrealistic, the anxious preoccupation persists.

Their concentration is often poor, and some experience difficulty with memory. At night, their minds remain active so that they have difficulty in falling asleep, and when they fall asleep, they may do so in a fitful and interrupted manner.

There are multiple somatic symptomsOpens in new window that a patient may also experience, including muscular tension, aches, fatigue, increased agitation, irritability, restlessness, trembling, and difficulty relaxing.

Signs of autonomic hyperactivity may also be present, including palpitations, sweating, hyperventilation with accompanying chest tightness, lightheadedness, and paresthesias. Gastrointestinal symptoms may also be present including abdominal distress, nausea, or diarrhea. Some patients may have increased urinary frequency. It may also affect their diet, with some people overeating and others restricting.

Diagnostic Criteria

Excessive worry is the hallmark of this GAD. In order to diagnose GAD, the symptoms must have persisted for at least 6 months. A person must experience multiple psychological and somatic symptoms during this time. These include muscle tension, restlessness, easy fatigue, difficulty concentrating, irritability, and sleep disturbances.

While these symptoms can coexist with other disorders, the anxiety experienced must be distinguished from other DSM-5 disorders. For instance, the patient’s anxietyOpens in new window and ruminationsOpens in new window cannot be about having a panic attackOpens in new window as in panic disorderOpens in new window, social situations as in social anxiety disorderOpens in new window or obsessionsOpens in new window as in OCDOpens in new window. Rather, the worries are about real life circumstances, albeit exaggerated.

Another important feature of the diagnostic criteria is that the symptoms should cause significant distress and may impair everyday functioning. The symptoms should not merely be the result of effects of drugs or alcohol or general medical conditions that can present in the same way.

Epidemiology

Epidemiological data suggest that the 1-year prevalence rate of GAD is around 2.6%, with a lifetime prevalence rate of 6.2%. Since this condition may seem like normal worry, it is underdiagnosed.

As with many other mood and anxiety disorders, women are more commonly affected than men. There is also a high comorbidity rate (50% or more) with depression and other anxiety disorders.

Patients often present to primary care providers with either somatic complaints that are related to the underlying anxiety (e.g., insomnia or fatigue), or exaggerated concerns about their own health or that of significant others.

Together, this leads to overuse of the medical system and frustration on the part of both patient and provider. Unfortunately, only about one quarter of patients are diagnosed.

Etiology

Genetics and Biological Factors

The propensity for GAD is at least partially heritable, with strong influence of environmental factors. The influence of environment may be either early adversity or recent stressors. However, GAD shows significant concordance with the features of the emotionally reactive temperament (also referred to as neuroticism).

Temperament is partially heritable and may serve as the foundation of risk for GAD. Moreover, the propensity for exaggerated emotional reactivity to exogenous stressors increases the propensity for major depression; this may explain the high concordance between GAD and depression. In many, the GAD is the stable characteristic of personality, with intermittent episodes of depression related to recent stress. Therefore, the evidence of genetic risk, anxiety, and depression may reflect the interaction of genetically derived temperament and life adversity.

In fact, the distress-related symptoms of GAD are commonly found in other conditions. Therefore, GAD has almost complete overlap with the symptoms of other mood and anxiety disorders. It is the specific symptoms of those disorders that distinguish them from GAD.

GAD shares symptom with other anxiety disorders and involves similar neural substratesOpens in new window. For example, exposure to pictures of anxious faces heightens activity of the amygdale.

Additionally, functional imaging studies have linked increased insular cortex activation to the brain’s processing of affects, such as fear and sadness; it also affects how cognitive processing and behavioral responses are linked.

Because GAD shares similar symptomology with other anxiety disorders, it should not be too surprising that similar neurochemical pathways and anatomical structures are involved as well.

SerotoninOpens in new window and GABAOpens in new window systems have been implicated in GAD; this may reflect more on the effects of psychotropic drugs than the actual causal dysregulation of brain function.

As noted in the general discussion of the neural substrateOpens in new window, anxiety is a normal response to certain situations. It is regulated by many distributed and interacting brain systems, as well as the neurotransmitters serotonin, GABA, and others. Therefore, dysregulation in any of several different modulators of the anxiety apparatus may result in persistent anxiety symptoms.

Psychological Factors

The prominent psychological feature of GAD is the propensity toward anticipation of future negative events. This is coupled with playing out plans to respond to the potential events. Because the fears are exaggerated, the person spends a great deal of psychological energy in the constant “contingency planning.”

The question, then, is why does that occur in the first place?

As noted earlier, GAD appears to derive, in part, from temperamental features of high emotional reactivity to stress—either real or anticipated. This pattern of reactivity can be seen as an aversive conditioning paradigm.

That is, in past adversity, the person experienced high anxiety that was difficult to control. This, then, represents a negative conditioning paradigm in which the person develops fears of possible future stressors. This becomes further reinforced in at least two ways. First, the worry itself causes distress, which heightens subsequent fear. However, occasionally the fear is realized, in which case future negative expectation is reinforced. Curiously, even though most fears do not come to pass, the occasional accurate prediction overrides extinction, and the worry persists.

There also is a kind of self-fulfilling natureOpens in new window to the problem as well. That is, that the fears lead to a modification of future behavior which may increase the likelihood of the event actually occurring.

An example would be a person who fears abandonment by a girlfriend or boyfriend. The person may become obsessed with the person’s fidelity, repeatedly challenging their faithfulness. Simultaneously, the person may engage in “clinging” behavior, such as insisting on constantly knowing the whereabouts of the other. This leads to frustration in the other person, and an eventual demise of the relationship. The fear, then, fulfills itself.

Pharmacological Treatment

SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs)Opens in new window, are the most commonly prescribed pyschotropicsOpens in new window for the treatment of generalized anxiety disorder.

People with GAD as a rule are not as sensitive to side effects as those with panic disorderOpens in new window. However, many of the same principles apply: first, start the dose relatively low, and, then, advance as required and tolerated. The notion is to reduce the anxiety to normal levels, allowing the person to live a normal life.

The drugs approved for the treatment of GAD are listed in Table X-1. While it should be noted that paroxetine and escitalopram are the only SSRIs with FDA indications for GAD, head-to-head randomized controlled trials (RCT) showed comparable efficacy between escitalopram, sertraline, and the SNRI venlafaxine XR.

Table X-1. Medications with FDA indications for generalized anxiety disorder.
Medication	Starting dosage	Recommended daily dosage
SSRIs
Paroxetine Citalopram Escitalopram	10 mg daily 10 mg daily 10 mg daily	20 – 50 mg 10 – 40 mg 10 – 20 mg
Buspirone	7.5 mg bid^α	30 – 60 mg daily^b
SSRI/SNRI
Venlafaxine XR Duloxetine	37.5 mg daily 20 mg daily	75 – 225 mg 30 – 60 mg
Note that table applies to regular adult dosing. Pediatric and geriatric dosing will be different, and may not be indicated. ^αTwice per day. ^b Usually given in a divided dose 15 – 30 mg twice per day.

BuspironeOpens in new window is a serotonin 1A receptor partial agonist, and has a moderate anti-anxiety effect. It is generally well tolerated and it has a low potential for sexual side effects. Furthermore, it does not have the potential for dependency or withdrawal reactions that plague benzodiazepinesOpens in new window. Therefore, it is a good initial choice for patients with GAD.

A number of benzodiazepines have indications for GAD and, in fact, have quite potent anti-anxiety effects. However, the effectiveness of benzodiazepines makes them highly reinforcing. Therefore, benzodiazepines have a high potential for dependency in this population.

Low potency benzodiazepines may be used on an as-needed basis early in the course of treatment with SSRIs or SNRIs. However, generally, other treatments, including antidepressantsOpens in new window, buspirone, or cognitive behavioral psychotherapy should be used prior to the regular use of benzodiazepines.

β-Adrenergic agents such as propranololOpens in new window have been used in the past to treat anxiety disorders. However, the effect is temporary and may facilitate the emergence of depression. Therefore, they should be avoided. Tricycline antidepressantsOpens in new window also are effective, but due to adverse side effects have given way to bitter tolerated agents such as the SSRIs.

Other antidepressants often tried in GAD include mirtazapineOpens in new window and bupropionOpens in new window. These are frequently used for patients who cannot tolerate the gastrointestinal or sexual side effects of SSRIs. There are currently no RCTs to support the treatment of GAD with mirtazapine, but there is one RCT supporting the efficacy of bupropion in GAD. Additionally, there si evidence to support the use of the anticonvulsant pregabalin, which has had 6 positive double blind RCTs supporting its use.

Psychological Treatment

Due to the complex environmental contribution in the development of GAD, psychoeducation and psychotherapy can prove helpful. Psychoeducation can identify lifestyle choices and life circumstances that can aggravate symptoms. For instance, many substances, such as caffeine, can lead to increased anxiety if consumed in large quantitites.

Various self-regulatory treatmenst such as biofeedback, relaxation, and meditation have been used with mixed results. Cognitive behavioral therapy has the most evidence demonstrating its efficacy in treating generalized anxiety disorder, and may be coupled with medication therapy.

Techniques of cognitive therapy include cognitive restructuring; that is, improved reality testing in appraisal of risk. This can be coupled with improving problem-solving skills and relaxation techniques.

There is preliminary evidence supporting mindfulness-based cognitive therapy for the treatment of GAD, but there has been no RCT yet to study this modality. This group therapy employs mindfulness meditation in a group setting and was shown to decrease both anxiety and depressive symptoms.

While there is only one study regarding its use specifically in GAD, one meta-analysis of 39 different studies showed an effect size of 0.97 for the treatment of anxiety symptoms across an array of medical and psychiatric diagnoses. Other therapies have limited empirical support.