Pharmacological treatment of generalized anxiety disorder (GAD)

Benzodiazepines.

Shortly after their introduction in the 1960s, benzodiazepines emerged as the treatment of choice for those experiencing generalized anxiety, though syndromal generalized anxiety disorder (GAD) would not be identifi  ed in the psychiatric nosology for nearly 20 years. Compared to other alternatives, they offer the prominent advantage of rapid symptom relief. They do not appear, however, to provide effective relief from the core symptoms of worry experienced by those with GAD, and some patients, particularly the elderly, have difficulty tolerating certain of their side effects such as sedation, impaired physical coordination increasing the risk for falls, poor concentration, and potentiation of the effects of alcohol. We consequently avoid using benzodiazepines in such patients; however, when benzodiazepines must be used in susceptible patients, agents that can be more readily cleared, that is, those without active metabolites and without very long half-lives, including lorazepam (Ativan) and oxazepam (Serax), are preferred. Finally, the dependence and addictive liability of benzodiazepines must be factored into any treatment decision regarding these agents.

Unlike the intermittent nature of panic attacks, the symptoms of GAD persist throughout the day. Consequently, longer-acting benzodiazepines, for example, chlordiazepoxide (Librium), clonazepam (Klonopin, Rivotril), clorazepate (Tranxene), and diazepam (Valium), have been most widely used. Longer-acting agents minimize both the need for multiple doses during the course of the day and the potential for interdose symptom reemergence. Surprisingly, the short-acting agent alprazolam (Xanax) has also found widespread use for GAD, typically administered in three to four divided doses per day. The recent introduction of extended-release alprazolam (Xanax ER) is likely suitable for GAD.

When initiating benzodiazepine treatment for GAD, tolerability can be im proved by starting at a low dose and gradually titrating to the effective dose range over the course of several days. Most patients with GAD respond well to 1–3 mg/day of extended-release alprazolam, 1–2 mg/day of clonazepam, or 10–20 mg/day of diazepam. Elderly patients often do best at approximately half these daily doses.

Because GAD is a chronic illness, benzodiazepines are often used in long-term maintenance therapy, leading to physical dependence over the course of several weeks. Consequently, abrupt discontinuation of a benzodiazepine can result not only in rebound anxiety and a rapid relapse but an acute benzodiazepine withdrawal syndrome as well. Refer to Chapter 6 for a more extensive discussion of benzodiazepine withdrawal. A very slow tapering over several weeks, if not months, is often required in order to discontinue a benzodiazepine so that the patient does not experience prominent withdrawal symptoms. An inpatient admission for benzodiazepine detoxifi  cation is sometimes necessary.

Tricyclic Antidepressants (TCAs).

Although the TCAs were introduced in the 1950s and 1960s, they were not formally tested in the treatment of GAD until the late 1980s. Controlled studies demonstrated that imipramine and clomipramine are effective in the treatment of GAD. They were outperformed by benzodiazepines at the end of the initial 2 weeks of therapy but actually provided greater benefi  t than benzodiazepines after 6 or more weeks of treatment. Due to the prominent side effects and danger in toxicity associated with TCAs, they have been supplanted by the newer generation of antidepressants, such as the SSRIs and SNRIs, as preferred agents in the treatment of generalized anxiety disorder. Refer to Chapter 3 for more information regarding TCAs.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-norepinephrine Reuptake Inhibitors (SNRIs).

The SSRI antidepressants, together with venlafaxine, have replaced the benzodiazepines as treatments of choice for GAD. Paroxetine and escitalopram are FDA approved for GAD, though it is generally believed that all SSRIs and SNRIs are effective for GAD. Similar to the TCAs, SSRIs/SNRIs appear to be most effective for the intrapsychic symptoms of GAD but less effective than benzodiazepines for the somatic manifestations of the disorder.

SSRI and SNRI onset of action is delayed by several weeks, and transient anxiety or agitation can be experienced during the fi  rst week of treatment. This problem can be avoided when treating GAD, as in other anxiety disorders, by initiating these agents at a daily dose that is approximately half that used when treating depression. This transient agitation aside, SSRIs and SNRIs are generally well tolerated by patients with GAD, and initial reports indicate that they are safe and effective as a long-term maintenance treatment for the disorder. Refer to Chapter 3 for a more extensive discussion of these agents.

Extended-release venlafaxine (Effexor XR), an antidepressant that blocks the reuptake of both serotonin and norepinephrine, has also obtained FDA approval for the treatment of GAD. Controlled studies indicate that venlafaxine is effective both in the acute treatment of GAD and as a longer-term maintenance therapy. Indeed, as noted earlier, like the SSRIs, venlafaxine has a delayed onset of action and can cause transient anxiety and agitation during the fi  rst week of therapy, particularly if the dose is too aggressively increased. When treating GAD, extended-release venlafaxine should be started at 37.5 mg taken as a single daily dose in the morning. It can gradually be titrated, as tolerated, to the effective dose range of 75–300 mg/day. Venlafaxine side effects are similar to those witnessed with SSRIs. Clinically signifi  cant blood pressure elevation can arise when the daily dose of venlafaxine exceeds 300 mg/day. Refer to Chapter 3 for more information regarding venlafaxine.

A controlled trial of duloxetine (Cymbalta) — like venlafaxine a dual serotonin–norepinephrine reuptake inhibitor — in the treatment of GAD is currently underway. Anecdotal data suggests that nefazodone (Serzone) and mirtazapine (Remeron) may be effective in the treatment of GAD, though no controlled data is available. In addition, recent concerns regarding nefazodone and liver toxicity have limited this medication’s utility. Please refer to Chapter 3 for more information regarding these antidepressants.

Buspirone (Buspar).

The first nonsedating, nonbenzodiazepine specifi  cally introduced as an anxiolytic, buspirone is FDA approved for the treatment of GAD. This medication acts as a partial agonist at the postsynaptic serotonin (5HT)-1A receptor. Like the antidepressants, buspirone has a delayed onset of action and effectively relieves the intrapsychic symptoms of GAD. Devoid of the muscle-relaxing properties of benzodiazepines, buspirone does not as effectively relieve the physical symptoms of GAD. Buspirone is not effective in the treatment of depression. Furthermore, its utility for the treatment of anxiety disorders other than GAD appears to be limited.

Buspirone does not share any of the problematic benzodiazepine properties such as sedation, motor impairment, addiction, physical dependence, or withdrawal. The most common side effects of buspirone include dizziness, nausea, headache, fatigue, and dry mouth. Despite its activity in the serotonin system, buspirone is not associated with the sexual side effects that plague the SSRIs, SNRIs, MAOIs, and TCAs.

There are two principal disadvantages of buspirone therapy. First, it must be administered two or three times daily. Long-term patient compliance is notoriously poor for medications that cannot be administered in a single daily dose. Second, buspirone is not an effective treatment for depression or any of the other comorbidities that frequently accompany GAD. As a result, buspirone monotherapy is only an alternative for GAD patients who have no comorbid illness.

The typical starting dose for buspirone is 15–20 mg/day, administered either as a regimen of 5 mg taken three times each day or 10 mg taken twice daily. The efficacy of buspirone is typically maximized at a daily dose of 30–60 mg. The maximal daily dose of 60 mg can be administered either as 20 mg taken three times daily or 30 mg taken twice daily.

Other Medications.

  A recent controlled GAD study revealed that pregabalin at a daily dose of 600 mg/day outperformed placebo and compared favorably to lorazepam, 6 mg/day. After 4 weeks of treatment, the participants assigned to pregabalin reportedly tolerated a 1 week taper better than those taking lorazepam. The most common pregabalin side effects reported in this study were sedation, weight gain, and dizziness. Although it is too early to recommend pregabalin for routine use for GAD, it may emerge as a favorable alternative to the benzodiazepines. It already warrants consideration for GAD patients who have not responded to other treatments.

Controlled studies of tiagabine in the treatment of GAD are currently underway.

Antihistamines.

  The antihistamine hydroxyzine (Vistaril, Atarax) has been used to manage anxiety. A typical regimen is 25 mg hydroxyzine administered one to three times per day as needed for anxiety. There is no evidence that hydroxyzine acts in any way to relieve anxiety other than by producing drowsiness. We do not recommend routine use of this treatment.