Anxiety disorders, the most prevalent psychiatric illnesses in the general community, are present in 15 to 20% of medical clinic patients. Anxiety, defined as a subjective sense of unease, dread, or foreboding, can indicate a primary psychiatric condition or can be a component of, or reaction to, a primary medical disease. The primary anxiety disorders are classified according to their duration and course and the existence and nature of precipitants.

When evaluating the anxious patient, the clinician must first determine whether the anxiety antedates or postdates a medical illness or is due to a medication side effect. Approximately one-third of patients presenting with anxiety have a medical etiology for their psychiatric symptoms, but an anxiety disorder can also present with somatic symptoms in the absence of a diagnosable medical condition.

Panic Disorder

Clinical Manifestations

Panic disorder is defined by the presence of recurrent and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, shortness of breath, chest pain, dizziness, and a fear of impending doom or death (Table 371-1). Paresthesias, gastrointestinal distress, and feelings of unreality are also common. Diagnostic criteria also require at least 1 month of concern or worry about the attacks or a change in behavior related to them. The lifetime prevalence of panic disorder is 1 to 3%. Panic attacks have a sudden onset, developing within 10 min and usually resolving over the course of an hour, and they occur in an unexpected fashion. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and results in a generalized fear and a progressive avoidance of places or situations in which a panic attack might recur. Agoraphobia, which occurs commonly in patients with panic disorder, is an acquired irrational fear of being in places where one might feel trapped or unable to escape (Table 371-2). Typically, it leads the patient into a progressive restriction in lifestyle and, in a literal sense, in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus physicians will fail to recognize the syndrome if direct questioning is not pursued.

Differential Diagnosis
A diagnosis of panic disorder is made after a medical etiology for the panic attacks has been ruled out. A variety of cardiovascular, respiratory, endocrine, and neurologic conditions can present with anxiety as the chief complaint. Patients with true panic disorder will often focus on one specific feature to the exclusion of others. For example, 20% of patients who present with syncope as a primary medical complaint have a primary diagnosis of a mood, anxiety, or substance-abuse disorder, the most common being panic disorder. The differential diagnosis of panic disorder is complicated by a high rate of comorbidity with other psychiatric conditions, especially alcohol and benzodiazepine abuse, which patients initially use in an attempt at self-medication. Some 75% of panic disorder patients will also satisfy criteria for major depression at some point in their illness.

When the history is nonspecific, physical examination and focused laboratory testing must be used to rule out anxiety states resulting from medical disorders such as pheochromocytoma, thyrotoxicosis, or hypoglycemia. Electrocardiogram (ECG) and echocardiogram may detect some cardiovascular conditions associated with panic, such as paroxysmal atrial tachycardia and mitral valve prolapse. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function testing or with symptoms of irritable bowel syndrome.

Etiology and Pathophysiology
The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered autonomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30 to 45% of monozygotic twins, and genome-wide screens have identified suggestive risk loci on 1q, 7p15, 10q, 11p, and 13q. Acute panic attacks appear to be associated with increased noradrenergic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the 2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Agents that block serotonin reuptake can prevent attacks. It is theorized that panic-disorder patients have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack. Accordingly, therapeutic intervention involves altering the patient’s cognitive interpretation of anxiety-producing experiences as well as preventing the attack itself.

Treatment
Achievable goals of treatment are to decrease the frequency of panic attacks and to reduce their intensity. The cornerstone of drug therapy is antidepressant medication (Tables 371-3, 371-4, and 371-5). The tricyclic antidepressants (TCAs)imipramine and clomipramine benefit 75 to 90% of panic disorder patients. Low doses (e.g., 10 to 25 mg/d) are given initially to avoid transient increased anxiety associated with heightened monoamine levels. Selective serotonin reuptake inhibitors (SSRIs) are equally effective and do not have the adverse effects of TCAs. SSRIs should be started at one-third to one-half of their usual antidepressant dose (e.g., 5 to 10 mg fluoxetine, 25 to 50 mg sertraline, 10 mg paroxetine). Monoamine oxidase inhibitors (MAOIs) are also effective and may specifically benefit patients who have comorbid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, and the need to maintain a low-tyramine diet (avoidance of cheese and wine) have limited their use, however. Antidepressants typically take 2 to 6 weeks to become effective, and doses may need to be adjusted based upon the clinical response.

Because of anticipatory anxiety and the need for immediate relief of panic symptoms, benzodiazepines are useful early in the course of treatment and sporadically thereafter (Table 371-6). For example, alprazolam, starting at 0.5 mg qid and increasing to 4 mg/d in divided doses, is effective, but patients must be monitored closely, as some develop dependence and begin to escalate the dose of this medication. Clonazepam, at a final maintenance dose of 2 to 4 mg/d, is also helpful; its longer half-life permits twice-daily dosing, and patients appear less likely to develop dependence on this agent.

Early psychotherapeutic intervention and education aimed at symptom control enhances the effectiveness of drug treatment. Patients can be taught breathing techniques, can be educated about physiologic changes that occur with panic, and can learn to expose themselves voluntarily to precipitating events in a treatment program spanning 12 to 15 sessions. Homework assignments and monitored compliance are important components of successful treatment. Once patients have achieved a satisfactory response, drug treatment should be maintained for 1 to 2 years to prevent relapse. Controlled trials indicate a success rate of 75 to 85%, although the likelihood of complete remission is somewhat lower.

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Table 371 - 3. Antidepressants

Name         Usual Daily Dose, mg
SSRIs

Fluoxetine (Prozac)    10-80
Sertraline (Zoloft)    50-200
Paroxetine (Paxil)    20-60
Fluvoxamine (Luvox)    100-300
Citalopram (Celexa)    20-60
Escitalopram (Lexapro)  10-30
Duloxetine (Cymbalta)  20-60
Side Effects
Headache; nausea and other GI effects; jitteriness; insomnia; sexual dysfunction; can affect plasma levels of other meds (except sertraline); akathisia rare. Caution in children, adolescents given possible increased risk of suicidal ideation after therapy initiation.

Comments
Once daily dosing, usually in A.M.; fluoxetine has very long half-life; must not be combined with MAOIs

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Name         Usual Daily Dose, mg
TCAs

Amitriptyline (Elavil)    150-300
Nortriptyline (Pamelor)  50-200
Imipramine (Tofranil)    150-300
Desipramine (Norpramin)  150-300
Doxepin (Sinequan)      150-300
Clomipramine (Anafranil)  150-300

Side Effects
Anticholinergic (dry mouth, tachycardia, constipation, urinary retention, blurred vision); sweating; tremor; postural hypotension; cardiac conduction delay; sedation; weight gain

Comments
Once daily dosing, usually qhs; blood levels of most TCAs available; can be lethal in O.D. (lethal dose = 2 g); nortriptyline best tolerated, especially

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Name         Usual Daily Dose, mg
MAOIs

Phenelzine (Nardil)      45 - 90
Tranylcypromine (Parnate)  20 - 50
Isocarboxazid (Marplan)  20 - 60
Side Effects
Insomnia; hypotension; anorgasmia; weight gain; hypertensive crisis; tyramine cheese reaction; lethal reactions with SSRIs; serious reactions with narcotics

Comments
May be more effective in patients with atypical features or treatment-refractory depression

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Name         Usual Daily Dose, mg
Mixed norepinephrine/serotonin reuptake inhibitors

Venlafaxine (Effexor) 75 - 375

Side Effects
Nausea; dizziness; dry mouth; headaches; increased blood pressure; anxiety and insomnia

Comments
Bid-tid dosing (extended release available); lower potential for drug interactions than SSRIs; contraindicated with MAOIs
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Mirtazapine (Remeron) 15 - 45

Side Effects
Somnolence; weight gain; neutropenia rare

Comments
Once daily dosing

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Name         Usual Daily Dose, mg
Mixed-action drugs

Bupropion (Wellbutrin) 250 - 450

Side Effects
Jitteriness; flushing; seizures in at-risk patients; anorexia; tachycardia; psychosis

Comments
Tid dosing, but sustained release also available; fewer sexual side effects than SSRIs or TCAs; may be useful for adult ADD
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Trazodone (Desyrel) 200 - 600

Side Effects
Sedation; dry mouth; ventricular irritability; postural hypotension; priapism rare

Comments
Useful in low doses for sleep because of sedating effects with no anticholinergic side effects
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Nefazodone (Serzone) 300 - 600

Side Effects
Sedation; headache; dry mouth; nausea; constipation

Comments
Once daily dosing; no effect on REM sleep unlike other antidepressants

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Amoxapine (Asendin) 200 - 600
Side Effects
Sexual dysfunction

Comments
Lethality in overdose; EPS possible

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