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.

Adverse effects of benzodiazepines generally parallel their relative half-lives. Longer-acting agents, such as diazepam, chlordiazepoxide, flurazepam, and clonazepam, tend to accumulate active metabolites, with resultant sedation, impairment of cognition, and poor psychomotor performance. Shorter-acting compounds, such as alprazolam and oxazepam, can produce daytime anxiety, early morning insomnia, and, with discontinuation, rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely to habituate to the adverse psychomotor effects. Withdrawal from the longer half-life benzodiazepines can be accomplished through gradual, stepwise dose reduction (by 10% every 1 to 2 weeks) over 6 to 12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Physicians may need to switch the patient to a benzodiazepine with a longer half-life or use an adjunctive medication, such as a beta blocker or carbamazepine, before attempting to discontinue the benzodiazepine. Withdrawal reactions vary in severity and duration; they can include depression, anxiety, delirium, lethargy, diaphoresis, tinnitus, autonomic arousal, adventitious movements, and, rarely, seizures.

Buspirone is a nonbenzodiazepine anxiolytic agent. It is nonsedating, does not produce tolerance or dependence, does not interact with benzodiazepine receptors or alcohol, and has no abuse or disinhibition potential. However, it requires several weeks to take effect and requires thrice-daily dosing. Patients who were previously responsive to a benzodiazepine are unlikely to rate buspirone as equally effective, but patients with Head injury or dementia who have symptoms of anxiety and/or agitation may do well with this agent.

Administration of benzodiazepines to geriatric patients requires special care. Such patients have increased drug absorption; decreased hepatic metabolism, protein binding, and renal excretion; and an increased volume of distribution. These factors, together with the likely presence of comorbid medical illnesses and medication, dramatically increase the likelihood of toxicity. Iatrogenic psychomotor impairment can result in falls and fractures, confusional states, or motor vehicle accidents. If used, agents in this class should be started at the lowest possible dose, and effects should be monitored closely. Benzodiazepines are contraindicated during pregnancy and breast-feeding.

Anticonvulsants with GABAergic properties may also be effective against anxiety. Gabapentin, oxcarbazepine, tiagabine, pregabalin, and divalproex have all shown some degree of benefit in a variety of anxiety-related syndromes. Agents that selectively target GABAA receptor subtypes are currently under development; and it is hoped that these will lack the sedating, memory-impairing, and addicting properties of benzodiazepines.