Understanding Generalized Anxiety Disorder

The medical community has only recently begun to define the nature of anxiety and its impact on physical and mental health. Here, two specialists discuss the latest approaches to diagnosis and treatment.

By Herbert E. Ward, MD and Liana Urfer, MD

Since its formal recognition in 1980, generalized anxiety disorder (GAD) has become the focus of increasing attention. Estimates of the lifetime prevalence in the U.S. of this common and treatable condition range from 4% to 7%. Generalized anxiety disorder produces not only psychological distress and functional impairment but also a wide variety of physical symptoms that often lead to expensive and inconclusive tests and procedures.

It is important for clinicians to recognize that patients who are known to chronically worry and have multiple somatic symptoms may be suffering from GAD. Interestingly, the prevalence of this condition has been found to be as high as 22% among persons who seek health care services at a higher rate than the rest of the population. People who have the disorder often misinterpret their physical symptoms as signs of a medical problem. They may return repeatedly to their primary or urgent care physician to obtain further medical evaluation and treatment, but many of these patients are also reluctant to seek or accept referral to a psychiatrist. Therefore, it is often the primary or urgent care physician who will be presented with the challenge of identifying and treating GAD.

This review addresses the diagnostic hallmarks and current treatment options for GAD and explains the medical and psychiatric differential diagnoses for the condition. It also provides guidelines for pursuing consultation or referral for more complicated cases.

EXCESSIVE ANXIETY AND WORRY

The current Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV), defines GAD as an anxiety disorder characterized by excessive anxiety and worry that lasts for a period of at least six months. These feelings are related to the various events and activities of everyday life, but for patients with GAD, they are difficult to control and of such intensity as to be considered by most people out of proportion to their cause.

Generalized anxiety disorder is also indicated by at least three of six additional, somatic symptoms, which include restlessness, easily induced fatigue, difficulty concentrating, irritability, muscle tension, and disturbed sleep (see table below). The entire constellation of symptoms produces significant distress and impairment in a patient's ability to function. The diagnosis is also strongly suggested when these symptoms cannot be linked to another psychiatric disorder, such as social phobia, or to the physiologic effects of a harmful substance or medical condition.

A review of the DSM-IV diagnostic criteria for GAD suggests the diagnosis is relatively straightforward. In clinical practice, however, the evaluation is more challenging, because patients are usually unaware that their symptoms are related to GAD. A useful screening strategy is to ask patients during a routine examination about life situations or conditions that might cause them anxiety. Beginning with the simple question "Do you consider yourself to be a worrier?" can be quite effective. Those who say yes should be prompted to discuss the nature of their concerns. Patients who have GAD tend to worry about many common problems-employment, finances, the health and safety of family and friends, and the ability to complete chores and errands on time, to give just a few examples-but their anxiety may be revealed by the exaggerated or disproportionate intensity they focus on such problems.

Unlike patients who have a simple or social phobia, those with GAD experience a free-floating anxiety that is not triggered by a specific fear, such as a fear of heights or public speaking. Most of them also do not have the brief, discrete episodes of extremely heightened anxiety that indicate panic disorder, although that condition is not uncommon among such patients; the estimated prevalence ranges from 3% to 27%. Indeed, other anxiety disorders often accompany GAD: simple phobia has been noted in 21% to 55% of affected patients and social anxiety in 16% to 59%. Nevertheless, clinicians should be aware that many patients with GAD have no specific anxiety disorder.

SOMATIC SYMPTOMS OF GAD

Many patients who have GAD do not acknowledge the psychological manifestations of the condition as readily as they do the somatic symptoms, which can involve almost any organ system. As a result, clinicians must often help their patients recognize the true nature of these somatic symptoms.

Particularly prominent among them are conditions associated with autonomic overactivity and hyperarousal. Patients often report excessive perspiration, hot flashes, tremulousness, difficulty concentrating, restlessness, and being easily startled. Typical cardiac symptoms include palpitations, chest pain, and a feeling of fainting. Shortness of breath is a classic pulmonary symptom. Among the many gastrointestinal symptoms of GAD are nausea, heartburn, diarrhea, constipation, and abdominal distension. Musculoskeletal symptoms include generalized muscle tension, neck and back pain, tension headache, and fatigue. Common genitourinary symptoms include urinary frequency, sexual dysfunction, and menstrual irregularities. Sleep disturbance is frequently reported.

In most cases, GAD begins in early adulthood and follows a chronic and fluctuating course. Symptoms will often worsen in response to stressful situations and abate in times of relative stability. Patients will often say they have had symptoms of anxiety dating back to childhood. In some cases, the initial episode can occur later in life. In the elderly, GAD rarely exists by itself; instead, it is usually associated with depression.

As a group, patients with untreated GAD are likely to experience not only significant impairment in their quality of life but also an increased risk of illness and death. Therefore, the positive impact of identifying and treating GAD at any point in the lifespan of an affected patient can be quite profound.

STIGMA OF PSYCHIATRIC DIAGNOSES

When evaluating patients who might have GAD, clinicians should be aware of the stigma associated with psychiatric diagnoses. Patients suffering from long-standing symptoms of GAD that have been misattributed to medical ailments may question or resist such a diagnosis. That reaction can present a substantial obstacle to treatment and may even lead the patient to seek another clinician in an attempt to shift the focus back to discrete somatic complaints.

Often, such patients can be reassured by comparing the features and treatment of GAD with those of common nonpsychiatric chronic illnesses like hypertension or diabetes. Also helpful is a brief explanation of the concepts of autonomic overactivity and the resultant hyperaroused state seen in GAD. By stressing the variety of effective psychopharmacologic and psychotherapeutic options, the clinician is more likely to encourage and motivate a patient toward trying a course of treatment.

BENZODIAZEPINE THERAPY: RAPID ONSET

Three types of medications are available to the clinician for treating GAD: benzodiazepines; buspirone, an azapirone; and antidepressants. All three have been shown to be effective, but the onset of anxiolytic action varies significantly. When choosing among them, clinicians must consider a patient's clinical presentation and history carefully. Patients should be told that their symptoms will abate gradually and that a six-month period of treatment is usually necessary before a medication can be judged ineffective and discontinued. Psychotherapy, particularly cognitive behavioral therapy, is highly recommended and should be offered as an adjunct.

The benzodiazepines are well known for their anxiolytic qualities, and they have demonstrated significant efficacy in reducing the anxiety seen in GAD. Among the advantages of benzodiazepine therapy is the drug's rapid onset of action, particularly in relieving the somatic symptoms of GAD. The disadvantages include its potential for abuse and dependence and its propensity to produce sedation, secondary symptoms of depression, and psychomotor or cognitive impairment.

Because benzodiazepines are associated with a risk of abuse and dependence, many clinicians are reluctant to prescribe the drugs, but it is important to note that such abuse is most common among patients who have a history of abusing other substances, particularly alcohol. For that reason, clinicians must obtain a thorough history from each patient before initiating treatment. The consequences of benzodiazepine overdose alone are relatively benign, but in combination with alcohol such an overdose can be fatal.

When selecting a specific benzodiazepine, the half-life and metabolism of each agent should be considered (see table below). Lorazepam, oxazepam, and temazepam are metabolized rapidly via direct conjugation without active metabolites. Consequently, these drugs are better tolerated by the elderly and patients with liver disease.

As a general rule, agents with a short half-life are associated with a higher incidence and intensity of withdrawal symptoms. The short half-life, in combination with the "high" sometimes associated with rapid onset of action, increases the risk of abuse and dependence. Symptoms of benzodiazepine withdrawal include anxiety, irritability, agitation, tachycardia, tremor, dilated pupils, diaphoresis, ataxia, psychosis, and seizure. In addition to monitoring patients for evidence of withdrawal, clinicians should be alert for signs of benzodiazepine intoxication, such as loss of motor coordination and slurred speech, and abuse, which is suggested by a request for a higher dose, for example, or premature refilling of a prescription.

To reduce the risk of abuse and dependence, clinicians should administer benzodiazepines as a short-term therapy for the relief of acute symptoms of anxiety. Concurrent long-term therapy consisting of either buspirone or an antidepressant is often prudent. This combination therapy allows a patient to receive the immediate benefit of the benzodiazepine while waiting for the other agent to take effect.

When benzodiazepine therapy must be discontinued, it is important that the patient adhere to a tapering schedule. Reducing the daily dosage by 25% each week is considered to be a safe and conservative approach that is unlikely to cause adverse effects.

In some cases, unfortunately, patients who have GAD do not respond to any medication except benzodiazepine, a situation that warrants a frank discussion between the clinician and patient about the benefits and risks of long-term benzodiazepine therapy.

BUSPIRONE: NO ABUSE POTENTIAL

The only member of the azapirone class of medications marketed in the United States, buspirone was developed as an antianxiety agent that carries no abuse potential. In contrast with benzodiazepines, this drug does not act rapidly, affect psychomotor function, or cause significant sedation. In addition, it has the advantage of not interacting with alcohol or other central nervous system (CNS) depressants. These qualities make buspirone a good choice for patients who have GAD who cannot tolerate the adverse affects of a benzodiazepine.

Numerous studies have demonstrated benzodiazepines and buspirone to be similarly efficacious in the treatment of GAD, but benzodiazepines appear to relieve the somatic symptoms of GAD more rapidly, while buspirone may be more beneficial in treating the psychological symptoms. Compared with those who have not undergone benzodiazepine therapy, patients who had used benzodiazepines previously to treat GAD often report less of a benefit from buspirone.

Before administering buspirone therapy, clinicians should emphasize certain points to their patients: Clinical response does not usually occur until two to four weeks after therapy is begun, and up to six weeks may be necessary for the drug to achieve its full effect. If taken only as needed, buspirone is not effective in treating anxiety. Patients who are accustomed to the rapid anxiolytic action of benzodiazepines may have difficulty adjusting their expectations. The usually prudent strategy for them, therefore, is to maintain a preexisting benzodiazepine regimen during the first few weeks of buspirone therapy.

The standard therapeutic buspirone dosage is 30 to 60 mg a day in three doses, although some evidence indicates two doses a day may be equally effective. It is best to have patients step up to this dosage gradually to minimize adverse effects, the most common of which are dizziness, headache, nausea, paresthesias, and anxiety. The recommendation is to begin with 5 mg three times daily with meals for the first week. The dose can then be increased by 5 mg every two to four days. To facilitate dosage adjustment, each 15-mg "dividose" tablet is scored to allow divided doses in 7.5- or 5-mg segments.

ANTIDEPRESSANT THERAPY

Researchers have been documenting the growing rate at which anxiety is accompanied by depression. Some estimate that in the U.S., major depressive disorder (MDD) occurs concurrently with GAD in more than 50% of cases. Within the psychiatric community, the necessity of recognizing "mixed anxiety and depression" as a new diagnosis is currently under debate. Because the first onset of GAD tends to occur early in life, some researchers have postulated that the disorder may even be a precursor to MDD.

The theory that symptoms of depression and anxiety may be manifestations of a single disease rather than of two distinct disorders has been supported further by growing evidence indicating that patients who have GAD respond positively to antidepressant medication. The potential advantage of a medication that treats both types of conditions is obvious.

To treat GAD most effectively with antidepressant therapy, clinicians should be familiar with the specific characteristics of the different agents (see table below). Generally speaking, antidepressants take two to four weeks to produce a clinical response. In addition, antidepressants are more effective than benzodiazepines in alleviating the psychological symptoms of GAD.

When beginning antidepressant therapy, patients should use a "start low, go slow" approach; increasing the dosage too rapidly can exacerbate anxiety symptoms. When discontinuing any antidepressant therapy, they should also gradually reduce the dosage to avoid adverse effects, particularly increased anxiety.

Venlafaxine. Extended-release venlafaxine is the only antidepressant currently FDA-approved for the treatment of GAD, although many other antidepressants are commonly prescribed for this condition. A relatively new agent, venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that has proved effective in the treatment of both MDD and GAD. Usually, the agent is tolerated very well, but because it does cause a distinctive dose-related elevation in diastolic blood pressure in approximately 5% of patients, clinicians should regularly monitor the blood pressure of patients taking the drug. Other adverse effects include nausea, dizziness, headache, and disturbed sleep.

The usual initial dosage is 37.5 to 75.0 mg daily, which can be increased by 37.5 to 75.0 mg every week until the therapeutic range of 150 to 225 mg daily is reached.

Selective serotonin reuptake inhibitors (SSRIs). The SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, and citalopram. Although these agents have been prescribed widely for the treatment of depression and have proved effective in treating many anxiety disorders-such as obsessive-compulsive, panic, social anxiety, and posttraumatic stress disorders-they have yet to receive FDA approval for the treatment of GAD.

Compared with the older tricyclic antidepressant agents (TCAs) and monoamine oxidase inhibitors (MAOIs), the SSRIs have a much more desirable adverse effect profile and are significantly less toxic in the event of an overdose. The agents are, however, commonly associated with specific adverse reactions, including headache, gastrointestinal distress, disturbed sleep, and sexual dysfunction. Additionally, patients frequently describe a sense of restlessness after starting SSRI therapy, particularly during the initial phase of treatment. Although this activating effect can sometimes be ameliorated by reducing the dosage, it may be intolerable to the patient who has GAD. This phenomenon emphasizes the importance of altering the drug dosage gradually when initiating and discontinuing SSRI therapy.

Mirtazapine and nefazodone. Like venlafaxine, mirtazapine and nefazodone enhance both serotonin and norepinephrine neurotransmission, but through different mechanisms of action. Both drugs produce relatively few adverse sexual effects. The adverse effects associated with nefazodone therapy are fairly benign; somnolence and gastrointestinal symptoms such as nausea and constipation are most common. Patients can alleviate the somnolence problem by taking most of the daily dose at bedtime. Mirtazapine is associated with two adverse effects, sedation and weight gain, which often lead patients to discontinue therapy. The sedating effect is inversely related to the dose-that is, patients will feel more sedated from the starting dose of 15 mg than from higher maintenance doses. Compliance with therapy is usually improved when this phenomenon is explained at the start of treatment. Mirtazapine should be taken at bedtime.

Older antidepressants. The TCAs and MAOIs do produce anxiolytic effects, but agents in both classes also produce well-known adverse effects such as orthostatic hypotension, dry mouth, sedation, and weight gain. In addition, a TCA overdose can be fatal, and patients who are taking MAOIs must adhere strictly to an essentially tyramine-free diet. The potential for significant drug interactions associated with these agents further complicates their use. Because all these drawbacks make TCAs and MAOIs less desirable-to patients and clinicians alike-than the newer antidepressant agents, they are usually reserved for patients whose disorder is resistant or refractory to treatment with the newer agents.

EFFICACY OF PSYCHOTHERAPY

Study data have repeatedly validated the efficacy of psychotherapy in the treatment of anxiety. In fact, some research has indicated that the benefits of psychotherapeutic therapy last longer than those provided by medications.

Patients who have GAD can clearly benefit from psychotherapy, particularly cognitive behavioral therapy, in which they identify the cognitive and behavioral patterns that contribute to their anxiety symptoms. Ultimately, the patients are taught how to alter those patterns and modify their response to the triggers of anxiety. Often incorporated into psychotherapy for the treatment of GAD are stress management training, relaxation exercises, breathing techniques, and distraction tasks.

The phenomenon of somatization is common in GAD. In that process, a psychological disturbance, such as anxiety, is expressed in the form of physical symptoms. Psychotherapy can often help patients who have GAD to identify their tendency for somatization and develop new and healthier ways of coping with anxiety.

It is important for the clinician to recognize that patients who have GAD often establish medical appointment patterns that reinforce somatization. By repeatedly making visits to a physician to address only physical complaints, patients will often obscure their underlying anxiety. For this reason, it is often preferable for the clinician to arrange follow-up appointments for these patients according to a regular schedule. Routine monthly visits, for example, scheduled regardless of whether a patient has somatic symptoms, will allow a clinician to shift the focus from physical to psychological issues. Such an approach can serve as a constructive first step in treating somatization in patients who have GAD.

MEDICAL AND PSYCHIATRIC DIFFERENTIAL DIAGNOSES

Because the medical differential diagnosis for anxiety is extremely broad, clinicians should consider other possible causes of a patient's symptoms before establishing the diagnosis of GAD. Among the many conditions to be ruled out, hyperthyroidism, CNS depressant withdrawal, and stimulant use are some of the most important (see table below).

However, an exhaustive investigation into the possible underlying medical causes is usually not necessary. In fact, treating GAD as a diagnosis of exclusion may serve only to perpetuate a patient's somatization and resistance to treatment. Even while considering other causes, the clinician should discuss with the patient the possibility of GAD. If a reasonable evaluation for other disease processes yields negative results, the diagnosis of GAD can then be discussed with the patient at greater length.

The psychiatric differential diagnosis for anxiety is also very broad. As mentioned earlier, GAD is very likely to occur concurrently with not only MDD but also with other anxiety disorders. Fortunately, as with MDD, these conditions can often be treated with the same agents used to treat GAD. For patients who have concomitant panic disorder and obsessive-compulsive disorder, however, the recommended medication regimens should be altered to include adjunctive short-acting benzodiazepine therapy for the former and high-dose SSRI therapy for the latter. In addition, clinicians should be aware that time-limited anxiety symptoms can sometimes occur in response to an acute stressor, in which case they are categorized diagnostically as an adjustment disorder with anxious mood.

REFERRAL AND CONSULTATION

As we have noted, clinical data show that most patients who have GAD usually seek care from their primary physicians rather than from mental health services. Consequently, primary and urgent care physicians are presented with frequent opportunities to diagnose and treat GAD. As we have summarized, several effective treatment options are available for patients who have GAD. The effectiveness of psychopharmacology and psychotherapy, either alone or in combination, has been well established.

Within the population of patients who have GAD, however, there are certain subgroups for whom a referral to or consultation with a psychiatrist is warranted. For a patient whose GAD seems to be refractory to adequate regimens of a benzodiazepine, buspirone, an SSRI, or one of the new antidepressants, a referral or consultation with a psychiatrist not only helps the physician confirm the diagnosis but also provides him or her with treatment recommendations. In addition, a psychiatric referral should be considered for patients who may benefit from therapy with a combination of psychotropic agents.