Generalized Anxiety Disorder

Clinical Manifestations

Patients with generalized anxiety disorder (GAD) have persistent, excessive, and/or unrealistic worry associated with muscle tension, impaired concentration, autonomic arousal, feeling "on edge" or restless, and insomnia (Table 371-7). Onset is usually before age 20, and a history of childhood fears and social inhibition may be present. The lifetime prevalence of GAD is 5 to 6%; the risk is higher in first-degree relatives of patients with the diagnosis. Interestingly, family studies indicate that GAD and panic disorder segregate independently. Over 80% of patients with GAD also suffer from major depression, dysthymia, or social phobia. Comorbid substance abuse is common in these patients, particularly alcohol and/or sedative/hypnotic abuse. Patients with GAD worry excessively over minor matters, with life-disrupting effects; unlike in panic disorder, complaints of shortness of breath, palpitations, and tachycardia are relatively rare.

Etiology and Pathophysiology

Experimental work suggests that anxiogenic agents share in common the property of altering the binding of benzodiazepines to the -aminobutyric acid (GABA)A receptor/chloride ion channel complex.

Benzodiazepines are thought to bind two separate GABAA receptor sites: type I, which has a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety effects of the various benzodiazepines and side effects such as sedation and memory impairment are influenced by their relative binding to type I and type II receptor sites. Serotonin [5-hydroxytryptamine (5HT)] also appears to have a role in anxiety, and buspirone, a partial 5HT1A receptor agonist, and certain 5HT2A and 5HT2C receptor antagonists (e.g., nefazodone) may have beneficial effects.

Treatment

A combination of pharmacologic and psychotherapeutic interventions is most effective in GAD, but complete symptomatic relief is rare. A short course of a benzodiazepine is usually indicated, preferably lorazepam, oxazepam, or temazepam. (The first two of these agents are metabolized via conjugation rather than oxidation and thus do not accumulate if hepatic function is altered.) Administration should be initiated at the lowest dose possible and prescribed on an as-needed basis as symptoms warrant. Benzodiazepines differ in their milligram per kilogram potency, half-life, lipid solubility, metabolic pathways, and presence of active metabolites. Agents that are absorbed rapidly and are lipid soluble, such as diazepam, have a rapid onset of action and a higher abuse potential. Benzodiazepines should generally not be prescribed for >4 to 6 weeks because of the development of tolerance and the risk of abuse and dependence. It is important to warn patients that concomitant use of alcohol or other sedating drugs may be neurotoxic and impair their ability to function. An optimistic approach that encourages the patient to clarify environmental precipitants, anticipate his or her reactions, and plan effective response strategies is an essential element of therapy.