Anxiety Disorders:

March 1, 2004
Thomas N. Wise, MD
Thomas N. Wise, MD

Millions of Americans suffer from anxiety disorders. Many with panic disorder, social anxiety disorder, and/or generalized anxiety disorder present initially to their primary care clinician. Effective treatment is possible in a busy primary care setting; therapy involves patient education and pharmacotherapy. Once other potential causes of symptoms of an anxiety disorder have been ruled out, the first step is to reassure the patient that he or she has a psychological condition-a very common one-and that symptoms are not the result of an undiagnosed disease or "going crazy" or "losing control." Educate and inform patients that complete clinical remission is achievable, often with medication alone. Begin treatment on day 1 with a long-acting benzodiazepine-such as alprazolam XR or clonazepam-or with the anxiolytic agent buspirone; at the same time, start a selective serotonin reuptake inhibitor (SSRI). The anxiolytic agent allays acute somatic symptoms until the full effects of the SSRI are manifest (often 4 to 6 weeks). The anxiolytic can then be gradually tapered. Referral to a psychiatrist for psychotherapy may be indicated when a patient refuses or cannot tolerate drug therapy, or when response to therapy is inadequate.


The patient is a 23-year-old woman who comes to her primary care physician's office concerned about periodic difficulty in breathing. She thinks she may have asthma.

She first experienced an attack of dyspnea while she was attending a special 2-week educational program for the state's top high school students; it was held about 2 hours from her home. During her stay, she experienced an episode in which she suddenly felt she was unable to breathe. School health officials thought she was having an asthma attack and sent her home. She was subsequently evaluated by her pediatrician. He detected minor wheezing on deep inspiration but ruled out asthma and attributed the attack to a possible allergy.

The patient experienced no further attacks for several years, until she left her parents' home for the first time to attend law school. She began to have repeated attacks of dyspnea and sought the advice of her primary physician.

During an attack, the patient feels as though she cannot breathe and that she is about to faint or die. Her heart races and she trembles. She worries that the episodes are a manifestation of an undiagnosed and perhaps life-threatening illness. The patient is embarrassed by these attacks and has not told anyone about them. However, dread of the next episode is now dominating her life and she fears she is "going crazy."


At his parent's insistence, a 22-year-old man seeks medical attention from his primary physician. He has just flunked out of college a second time. The parents want to understand the reasons behind their son's academic failure, and they fear that he may be abusing drugs. This fear was fueled, in part, by another physician who had previously evaluated the patient: the clinician had told the parents that their son was probably a "doper" and a "bad kid."

The patient had been popular and a good student in high school. He was an outstanding athlete. His parents reported that they had enjoyed living with him and that he had always been helpful around the house.

The patient reports that although he loves to coach sports, he is unable to get up in front of a group and teach. He finds it similarly difficult to speak in the classroom. He describes himself as "very shy" and reports that he is afraid people are laughing at him. Friends seek out his company, but he never pursues these relationships.

He reports that drinking was a "regular" part of daily campus life and that he had been using alcohol almost every day to the point of intoxication to cover up his shyness. His alcohol dependence led to his expulsion from school.

Case 3

The patient is a 54-year-old man who has been worrying excessively about activities of daily living in general and his health in particular for several years. He recently read about leukemia and asked his primary physician to perform a bone marrow aspiration to rule out the disease. A hypochondriac, he fears that his minor physical ailments (such as headaches, coughing, and sneezing) are masking a deadly disease. He is also convinced that his 33-year-old son, who is mildly overweight, is going to die soon of heart disease, and he is doing his utmost to convince his son to lose his excess weight.

The patient is a successful businessman, husband, and father of several children as well as an athlete, a painter-even a decorated war veteran. Despite his achievements, however, the patient feels "miserable" and "tortured" by his persistent worries. He anticipates and dreads poor outcomes of even routine activities. He feels he cannot go to the movies because he might be unable to get a parking spot. He is convinced that people disregard him because he is short. He believes his wife is entirely unsympathetic to his plight. He now seeks your medical advice.

Each of the patients in these case histories is suffering from an anxiety disorder. The young law student has panic disorder-a condition that has repeatedly caused autonomic hyperarousal and anticipatory anxiety but that went undiagnosed for a long period. The 22-year-old college dropout has developed an alcohol addiction secondary to social anxiety disorder (SAD). The 54-year-old patient's persistent worries are a manifestation of generalized anxiety disorder (GAD). In each case, an anxiety disorder has interfered with activities of daily living to the point that none of these patients are able to function normally.

Psychiatric disorders affect an estimated 44 million persons in this country, more than a third of whom have at least 1 anxiety disorder.1 The burden of anxiety disorders is high-both personally, as reflected in a loss of the patient's ability to carry on normally at home and on the job-and in economic terms. The estimated price of anxiety disorders (including the direct costs of drug therapy and psychiatric and nonpsychiatric treatment, and the indirect costs of lost work time and mortality) totaled $63.1 billion in 1998 dollars.1

The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines 6 distinct subcategories of anxiety disorder.2 Three of these-specific phobia, obsessive-compulsive disorder, and post-traumatic stress disorder-are usually outside the realm of primary care. However, persons with panic disorder, SAD, and GAD typically present to their primary physician with their emotional distress-and are thus the focus of this review.3-5 It is critical that primary care clinicians recognize these chronic disorders in their many somatic guises-and understand their debilitating impact on a patient's life. Knowledge of the various therapeutic options (medications, lifestyle measures, and cognitive behavioral therapy) and the ability to formulate an effective treatment plan are equally crucial.

My intent here is not to reiterate the details of diagnosis of these anxiety disorders, which have been elegantly described elsewhere.1-4,6,7 Nor is my goal to describe the details of psychotherapy, which, in the context of busy primary care, is usually the domain of the psychiatrist. Instead, the focus is on treatment-in particular, on pharmacotherapy that can be successfully employed in a primary care setting.


The widespread prevalence of anxiety disorders has been amply documented, as has their impact on the quality of a patient's life.4,6-8 Roughly 25% of those in the general population meet the criteria for an anxiety disorder at some point (Figure).9,10 Moreover, an anxiety disorder rarely exists in isolation and frequently coexists with a depression.11 For this reason, the DSM-IV includes mixed anxiety and depression as a distinct clinical entity.2 Clinicians thus need to consider the possibility of comorbid depression whenever they encounter an anxious patient.

Given their toll on a patient's psyche, it is fortunate that panic disorder, SAD, and GAD can be treated effectively. There are several therapeutic components, depending on the patient and the severity of his or her disorder (Algorithm).These include psychological reassurance, pharmacotherapy, and psychotherapy.

Reassurance. Many patients with anxiety disorders fear that their symptoms reflect a dire illness. For example, patients with panic disorder frequently attribute their rapid heart beat, dizziness, and difficulty in breathing to a "heart attack." These persons also fear that they are "losing control" and "going crazy."

Assuming that underlying physical causes have been ruled out, reassurance is the first therapeutic step and the key to patient education. In this setting, never tell a patient that "nothing is wrong": what is wrong is that he has an anxiety disorder-not a serious cardiac problem. The patient needs to understand that the symptoms are psychogenic, that he is not crazy, that anxiety disorders are very common, and that the symptoms can be treated. Failure to address the patient's need for understanding and reassurance-and to proceed straight ahead with drug therapy-is therapeutic folly.

Start an anxiolytic agent. Acute symptoms can be ameliorated with a high-potency, long-acting benzodiazepine, such as alprazolam or clonazepam. Buspirone, an azapirone, can also benefit anxious patients, particularly those with relatively mild symptoms; this agent is also a weak antidepressant.

Add an SSRI. Dual therapy with a selective serotonin reuptake inhibitor (SSRI) and an anxiolytic agent is a highly effective treatment strategy for anxious patients.12 Typically, combination therapy with a benzodiazepine and an SSRI is initiated on day 1; the patient is told that the benzodiazepine will be given for only a short time and then withdrawn gradually. After 4 to 6 weeks of dual therapy, the full therapeutic effect of the SSRI should be evident. At this point, the benzodiazepine can be tapered and SSRI monotherapy continued. (This approach was used successfully with all 3 patients in the case scenarios above.)

The benefits of this approach include immediate relief of somatic symptoms; the benzodiazepine typically ameliorates the restlessness that the SSRI can cause initially. Moreover, this approach eliminates such potential problems as benzodiazepine dependence and withdrawal symptoms.

SSRIs are now the mainstay of treatment of anxiety disorders. These agents have replaced the tricyclic antidepressants in this setting; the latter are associated with significant anticholinergic effects. The SSRIs that are currently indicated in the management of anxiety disorders are listed in the Table. Less is known about the role of escitalopram and fluvoxamine in anxious patients, and therefore these agents have been excluded from the Table.

Psychotherapy. Many patients do well with pharmacologic therapy alone. Others-including those with refractory symptoms or comorbid conditions-require ongoing psychotherapy, either as monotherapy or as an adjunct to drug treatment.13 This may include relaxation exercises, respiratory control techniques, and gradual but controlled exposure to feared stimuli.3,14

Whether psychotherapy is indicated for a particular patient depends on his willingness to take medication, the severity of the anxiety symptoms, and the presence of coexisting mental disorders (eg, depression).

Referral to a psychiatrist is indicated when the primary clinician lacks the time and/or expertise to administer psychotherapy. Behavioral therapy has been demonstrated to be effective, but other forms of psychotherapy may also help. Psychiatric referral is also warranted when a patient refuses or cannot tolerate drug therapy or when a patient's response to a 6- to 8-week trial of antidepressant/anxiolytic therapy is incomplete or inadequate.3,14


The goal of therapy is a robust and sustained clinical remission. Patients need to be told that they can recover normal function-not just temporarily, but over the long term. In the primary care setting, anxiety disorders are managed with an anxiolytic agent (either a benzodiazepine or an azapirone) and an antidepressant.

Benzodiazepines. These agents have long been used to treat anxiety and are considered first-line agents for a limited period. They are particularly effective in relieving acute anxiety. The long-acting, high-potency anxiolytic agents, clonazepam and alprazolam, are the most widely prescribed agents in this class for patients with an anxiety disorder.4 A variety of studies demonstrate that these agents are seldom abused, particularly among those patients who have no history of substance abuse15 and that the incidence of adverse effects is relatively low.

Benzodiazepines are not a panacea for patients with anxiety disorders, however. Their side effects may include sedation and impairment of sensory motor coordination, and their use can interfere with a patient's ability to perform such tasks as driving. These effects are particularly marked in elderly persons.

Habituation can be a problem with the benzodiazepines; the dosage may need to be escalated over time to achieve the same therapeutic effect. Moreover, these agents can potentiate the effects of alcohol.

The immediate-release formulations have relatively short durations of action and must be taken in multiple daily doses, which creates problems with patient compliance. Moreover, blood levels of the shorter-acting agents fluctuate significantly; this can result in breakthrough anxiety between doses. More consistent blood levels can be achieved with longer-acting benzodiazepines, such as alprazolam and clonazepam.

Many patients have significant difficulty in discontinuing use of these agents-particularly those who have taken a benzodiazepine at relatively high dosages and/or for relatively long periods. Withdrawal of the medication can precipitate rebound and exacerbate such withdrawal symptoms as anxiety, agitation, and sleep disturbances. This effect can generally be avoided by gradually tapering the dosage by 0.25 to 0.5 mg every 5 to 7 days.

The benzodiazepines are ineffective antidepressants. Because depression commonly coexists with an anxiety disorder, benzodiazepines are no longer given as monotherapy for long-term therapy for patients with coexisting anxiety and depression.

Azapirones. Buspirone also offers anxiolytic benefits-particularly to those with relatively mild symptoms-and, in particular, significantly diminishes the symptoms of generalized anxiety.16 This drug can exacerbate panic, however, and thus is not used in panic disorder. It is less sedating than the benzodiazepines but has a weak antidepressant effect.17 Buspirone is associated with less sexual dysfunction than the SSRIs16;it does not induce extrapyramidal side effects and does not appear to cause tolerance or withdrawal reactions.18 Drawbacks include its latency to efficacy; the drug's full therapeutic effect may not occur for 3 to 6 weeks.

SSRIs. The SSRIs are effective antidepressants and also effective anxiolytics and are therefore well suited to the long-term management of anxiety disorders and comorbid depression. Long-term use of one of these agents (over months or years) does not lead to dependence, which marks them in distinct contrast with the benzodiazepines.

These potent anti-panic agents affect the serotonin reuptake system but have different side-effect profiles. Some cause more sedation or more weight gain than others. The various agents are also associated with greater or lesser degrees of weight loss, sexual dysfunction, fatigue, asthenia, and blank affect. Patient education may afford you the opportunity to intervene when these effects first develop. In addition, all SSRIs are associated in various degrees with withdrawal or discontinuation syndromes that may evoke symptoms of anxiety or panic; consequently, they must be gently tapered.

The starting dosage for these agents in anxious patients is usually somewhat lower than those recommended for patients with depression. The adage, "start low and go slow" certainly applies in this setting. A general rule is to start with either one quarter or one half of the usual starting dose in patients with panic disorder, SAD, or GAD. Slowly taper the dosage upward; the effective dosage may be at least as high as that usually prescribed for management of depression.18

Serotonin and norepinephrine reuptake inhibition. Venlafaxine blocks neuronal uptake of serotonin and norepinephrine. Several randomized controlled trials have shown this medication to be an effective, rapid-acting, and safe agent in the long- or short-term treatment of anxiety in patients with or without comorbid depression.19,20 The drug is indicated in the treatment of depression and GAD and may be useful for patients in whom SSRI therapy has been ineffective.

It is important to note that venlafaxine significantly blocks norepinephrine reuptake only when the drug is given in dosages above 150 mg/d. This agent may cause hypertension. Also, like the SSRIs, venlafaxine is associated with sexual side effects and discontinuation syndrome.

The majority of anxious patients respond favorably to SSRI therapy. The effects of these agents usually become manifest within several weeks. However, roughly 1 in 3 are unable to tolerate these drugs or will have a partial therapeutic response.21,22 Moreover, about 40% stop taking their medication within 3 months.23,24 This is often the result of side effects. Thus, the clinician's task is to modify the symptoms of the anxiety disorder medically while recognizing that adverse effects may cause nonadherence. When side effects (such as sexual dysfunction, weight gain, or agitation) do occur, these can be managed by a drug change or by adding agents to counteract the problem. Referral to a psychiatrist is the first choice in this setting.



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