In all cases, underlying medical disorders must be ruled out (eg, cardiovascular, endocrine, respiratory, and neurologic disorders and substance-related syndromes, both intoxication and withdrawal states).
1. Generalized anxiety disorder
Antidepressants including the SSRIs and serotonin norepinephrine reuptake inhibitors (SNRIs) are first-line treatment and safe and effective in the long-term management of GAD. Some patients may find more noradrenergic SNRIs such as levomilnacipran too activating to tolerate. The antidepressants appear to be as effective as the benzodiazepines without the risks of tolerance or dependence. However, benzodiazepines take effect more quickly if not immediately, which can be beneficial in brief acute management (Table 25–1).
Table 25–1.Commonly used antianxiety and hypnotic agents (listed in alphabetical order within classes). ||Download (.pdf) Table 25–1. Commonly used antianxiety and hypnotic agents (listed in alphabetical order within classes).
|Medication ||Usual Daily Oral Doses ||Usual Daily Maximum Doses ||Cost for 30 Days of Treatment Based on Maximum Dosage1 |
|Benzodiazepines (used for anxiety) |
|Alprazolam (Xanax)2 ||0.5 mg ||4 mg ||$101.40 |
|Chlordiazepoxide (Librium)3 ||10–20 mg ||100 mg ||$42.00 |
|Clonazepam (Klonopin)3 ||1–2 mg ||10 mg ||$152.25 |
|Clorazepate (Tranxene)3 ||15–30 mg ||60 mg ||$560.40 |
|Diazepam (Valium)3 ||5–15 mg ||30 mg ||$22.50 |
|Lorazepam (Ativan)2 ||2–4 mg ||4 mg ||$5.46 |
|Oxazepam (Serax)2 ||10–30 mg ||60 mg ||$126.00 |
|Benzodiazepines (used for sleep) |
|Estazolam (Prosom)2 ||1 mg ||2 mg ||$29.70 |
|Flurazepam (Dalmane)3 ||15 mg ||30 mg ||$26.40 |
|Midazolam (Versed)4 ||5 mg || ||$1.24/dose |
|Quazepam (Doral)3 ||7.5 mg ||15 mg ||$738.00 |
|Temazepam (Restoril)2 ||15 mg ||30 mg ||$24.30 |
|Triazolam (Halcion)5 ||0.125 mg ||0.25 mg ||$110.00 |
|Miscellaneous (used for anxiety) |
|Buspirone (Buspar)2 ||10–30 mg ||60 mg ||$217.80 |
|Phenobarbital3 ||15–30 mg ||90 mg ||$33.90 |
|Miscellaneous (used for sleep) |
|Eszopiclone (Lunesta)5 ||2–3 mg ||3 mg ||$350.10 |
|Hydroxyzine (Vistaril)2 ||50 mg ||100 mg ||$24.60 |
|Ramelteon (Rozerem) ||8 mg ||8 mg ||$419.70 |
|Suvorexant (Belsomra) ||5–10 mg ||20 mg ||$438.90 |
|Zaleplon (Sonata)6 ||5–10 mg ||10 mg ||$112.50 |
|Zolpidem (Ambien)5 ||5–10 mg ||10 mg ||$137.10 |
Antidepressants are the first-line medications for sustained treatment of GAD, having the advantage of not causing physiologic dependency problems. Antidepressants can themselves be anxiogenic when first started—thus, at the initiation of treatment, patient education and at times concomitant short-term treatment with a benzodiazepine are indicated. SSRIs, such as escitalopram and paroxetine, are FDA-approved. The SNRIs venlafaxine and duloxetine are FDA-approved for the treatment of GAD in usual antidepressant doses. Initial daily dosing should start low (37.5–75 mg for venlafaxine and 30 mg for duloxetine) and be titrated upward as needed. While most antidepressants including tricyclic antidepressants (TCAs) and monoamine oxidase (MAO) inhibitors are often effective in the treatment of anxiety disorders, their side effects and drug interactions make them second- or third-line agents. Buspirone, sometimes used as an augmenting agent in the treatment of depression and compulsive behaviors, is also effective for generalized anxiety. Buspirone is usually given in a total dose of 30–60 mg/day in divided doses. Higher doses are sometimes associated with side effects of gastrointestinal symptoms and dizziness. Bupropion may be the most anxiogenic antidepressant and does not have evidence in treatment of anxiety disorders. There is a 2- to 4-week delay before antidepressants and buspirone take effect, and patients require education regarding this lag. Sleep is sometimes negatively affected. Gabapentin (titrated to doses of 900–1800 mg orally daily, with larger doses at night) appears effective and lacks the habit-forming potential of the benzodiazepines. Unfortunately, like buspirone, many patients find gabapentin less effective than benzodiazepines in the management of acute anxiety. Beta-blockers, such as propranolol, may help reduce peripheral somatic symptoms. Alcohol is the most frequently self-administered drug and should be strongly discouraged.
Antidepressants are the first-line pharmacotherapy for panic disorder. Several SSRIs, including fluoxetine, paroxetine, and sertraline, are approved for the treatment of panic disorder. The SNRI venlafaxine is FDA approved for treatment of panic disorder. As with GAD, panic disorder is often a chronic condition; the long-term use of benzodiazepines can result in tolerance or even benzodiazepine dependence. While panic disorder often responds to high-potency benzodiazepines such as clonazepam and alprazolam, the best use of these agents is generally early in the course of treatment concurrently with an antidepressant. Once the antidepressant has begun working after 4 or more weeks, the benzodiazepine may be tapered.
Whether the indications for benzodiazepines are anxiety or insomnia, the medications should be used judiciously. The longer-acting benzodiazepines are used for the treatment of alcohol withdrawal and anxiety symptoms; the intermediate medications are useful as sedatives for insomnia (eg, lorazepam), while short-acting agents (eg, midazolam) are used for medical procedures such as endoscopy. Benzodiazepines may be given orally, and several are available in intramuscular or parenteral formulations. In psychiatric disorders, the benzodiazepines are usually given orally; in controlled medical environments (eg, the intensive care unit [ICU]), where the rapid onset of respiratory depression can be assessed, they often are given intravenously. Lorazepam does not produce active metabolites and has a half-life of 10–20 hours; these characteristics are useful in treating elderly patients or those with liver dysfunction. Ultra–short-acting agents, such as triazolam, have half-lives of 1–3 hours and may lead to rebound withdrawal anxiety. Longer-acting benzodiazepines, such as flurazepam, diazepam, and clonazepam, produce active metabolites, have half-lives of 20–120 hours, and should be avoided in the elderly; however, some clinicians prefer clonazepam because of its long half-life and thus ease of dosing to once or twice a day. Since people vary widely in their response and since the medications are long lasting, the dosage must be individualized. Once this is established, an adequate and scheduled dose early in the course of symptom development will obviate the need for “pill popping,” which can contribute to dependency problems.
The side effects of all the benzodiazepine antianxiety agents are patient and dose dependent. As the dosage exceeds the levels necessary for sedation, the side effects include disinhibition, ataxia, dysarthria, nystagmus, and delirium. (The patient should be told not to operate machinery and drive with caution until he or she is well stabilized without side effects.)
Paradoxical agitation, anxiety, psychosis, confusion, mood lability, and anterograde amnesia have been reported, particularly with the shorter-acting benzodiazepines. These agents produce cumulative clinical effects with repeated dosage (especially if the patient has not had time to metabolize the previous dose), additive effects when given with other classes of sedatives or alcohol, and residual effects after termination of treatment (particularly in the case of medications that undergo slow biotransformation).
Overdosage results in respiratory depression, hypotension, shock syndrome, coma, and death. Flumazenil, a benzodiazepine antagonist, is effective in overdosage. Overdosage (see Chapter 38) and withdrawal states are medical emergencies. Serious side effects of chronic excessive dosage are development of tolerance, resulting in increasing dose requirements, and physiologic dependence, resulting in withdrawal symptoms similar in appearance to alcohol and barbiturate withdrawal (withdrawal effects must be distinguished from reemergent anxiety). Abrupt withdrawal of sedative medications may cause serious and even fatal convulsive seizures. Psychosis, delirium, and autonomic dysfunction have also been described. Both duration of action and duration of exposure are major factors related to likelihood of withdrawal.
Common withdrawal symptoms after low to moderate daily use of benzodiazepines are classified as somatic (disturbed sleep, tremor, nausea, muscle aches), psychological (anxiety, poor concentration, irritability, mild depression), or perceptual (poor coordination, mild paranoia, mild confusion). The presentation of symptoms will vary depending on the half-life of the medication. Benzodiazepine interactions with other medications are listed in Table 25–2.
Table 25–2.Benzodiazepine interactions with other medications (listed in alphabetical order). ||Download (.pdf) Table 25–2. Benzodiazepine interactions with other medications (listed in alphabetical order).
Antidepressants have been used in conjunction with beta-blockers in resistant cases. Propranolol (40–160 mg/day orally) can mute the peripheral symptoms of anxiety without significantly affecting motor and cognitive performance. They block symptoms mediated by sympathetic stimulation (eg, palpitations, tremulousness) but not nonadrenergic symptoms (eg, diarrhea, muscle tension). Contrary to common belief, they usually do not cause depression as a side effect and can be used cautiously in patients with depression.
Social phobias and agoraphobia may be treated with SSRIs, such as paroxetine, sertraline, and fluvoxamine. In addition, phobic disorders often respond to SNRIs such as venlafaxine. Gabapentin is an alternative to antidepressants in the treatment of social phobia in a dosage of 300–3600 mg/day, depending on response versus sedation. Specific phobias such as performance or test anxiety may respond to moderate doses of beta-blockers, such as propranolol, 20–40 mg 1 hour prior to exposure. Specific phobias tend to respond to behavioral therapies such as systematic desensitization, which is when the patient is gradually exposed to the feared object or situation in a controlled setting.
Behavioral approaches are widely used in various anxiety disorders, often in conjunction with medication. Any of the behavioral techniques can be used beneficially in altering the contingencies (precipitating factors or rewards) supporting any anxiety-provoking behavior. Relaxation techniques can sometimes be helpful in reducing anxiety. Desensitization, by exposing the patient to graded doses of a phobic object or situation, is an effective technique and one that the patient can practice outside the therapy session. Emotive imagery, wherein the patient imagines the anxiety-provoking situation while at the same time learning to relax, helps decrease the anxiety when the patient faces the real-life situation. Physiologic symptoms in panic attacks respond well to relaxation training. Both GAD and panic disorder appear to respond as well to cognitive behavioral therapy as they do to medications. Exercise, both aerobic and resistance training, have demonstrated effects in reducing anxiety symptoms across many anxiety disorders as well.
Cognitive behavioral therapy is the first-line psychotherapy in treatment of anxiety disorders. Cognitive behavioral therapy for anxiety disorders includes a cognitive component of examining the thoughts associated with the fear, and a behavioral technique of exposing the individual to the feared object or situation. The combination of medication and cognitive behavioral therapy is more effective than either alone. Mindfulness meditation can also be effective in decreasing symptoms of anxiety. Group therapy is the treatment of choice when the anxiety is clearly a function of the patient’s difficulties in dealing with social settings. Acceptance and commitment therapy have been used with some success in anxiety disorders. It encourages individuals to keep focused on life goals while they “accept” the presence of anxiety in their lives.
Peer support groups for panic disorder and agoraphobia have been particularly helpful. Social modification may require measures such as family counseling to aid acceptance of the patient’s symptoms and avoid counterproductive behavior in behavioral training. Any help in maintaining the social structure is anxiety-alleviating, and work, school, and social activities should be maintained. School and vocational counseling may be provided by professionals, who often need help from the clinician in defining the patient’s limitations.