Pharmacotherapy Of Anxiety

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Anxiety is a symptom of many psychiatric disorders and an almost inevitable component of many medical and surgical conditions. Symptoms of anxiety commonly are associated with depression and especially with dysthymic disorder (chronic depression of moderate severity), panic disorder, agoraphobia and other specific phobias, obsessive-compulsive disorder, eating disorders, and many personality disorders. Sometimes, no treatable primary illness is found, or if one is found and treated, it may be desirable to deal directly with the anxiety at the same time. In such situations, antianxiety medications are frequently and appropriately used.

Currently, the benzodiazepines and the SSRIs are the most commonly employed pharma-cotherapies for common clinical anxiety disorders (see Chapter 16). Benzodiazepines sometimes are given to patients presenting with anxiety mixed with symptoms of depression, although their efficacy in altering the core features of severe major depression has not been demonstrated.

The most favorable responses to the benzodiazepines are obtained in situations that involve relatively acute anxiety reactions in medical or psychiatric patients who have either modifiable primary illnesses or primary anxiety disorders. However, this group of anxious patients also has a high response rate to placebo and is likely to undergo spontaneous improvement. Antianxiety drugs also are used in the management of more persistent or recurrent primary anxiety disorders. A particularly controversial aspect of the use of benzodiazepines, especially those of high potency, is in long-term management of patients with sustained or recurring symptoms of anxiety; despite clinical benefit for at least several months, it is unclear if the long-term benefits can be distinguished from nonspecific ("placebo") effects following development of tolerance on the one hand, or prevention of related withdrawal-emergent anxiety on the other.

The antihistamine hydroxyzine is an effective antianxiety agent, but only at doses (~400 mg/day) that produce marked sedation (see Chapter 24). Propranolol and metoprolol, lipophilic b adrenergic receptor antagonists that enter the CNS, can reduce the autonomic symptoms (nervousness and muscle tremor) associated with specific situational or social phobias but do not appear to be effective in generalized anxiety or panic disorder (see Chapter 10). Similarly, other antiadrener-gic agents, including clonidine, may modify autonomic expression of anxiety but are not demonstrably useful in the treatment of severe anxiety disorders.

The azapirones (azaspirodecanediones) (e.g.,buspirone [buspar]) are useful in anxiety or dysphoria of moderate intensity. The azapirones have limited antidopaminergic actions in vivo, do not induce clinical extrapyramidal side effects, and do not interact with binding sites for benzodi-azepines or facilitate the action of GABA. They are not anticonvulsant (and may even lower seizure threshold slightly), do not appear to cause tolerance or withdrawal reactions, and do not show cross-tolerance with benzodiazepines or other sedatives. Buspirone and several experimental congeners (e.g., gepirone, ipsapirone, and tiospirone) have selective affinity for 5-HT receptors of the 5-HTia type, for which they appear to be partial agonists (see Chapter 11). Buspirone lacks beneficial actions in severe anxiety with panic attacks. The risk of suicide with buspirone is very low.

OTHER THERAPEUTIC USES OF THESE DRUGS The various antidepressant agents have found broad utility in other disorders that may not be related psychobiologically to the mood disorders. Current applications include rapid but temporary suppression of enuresis with low (e.g., 25 mg) pre-bedtime doses of tricyclic antidepressants, including imipramine and nor-triptyline, by uncertain mechanisms in children and in geriatric patients, as well as a beneficial effect of duloxetine on urinary stress incontinence. Antidepressants have a growing role in attention-deficit/hyperactivity disorder in children and adults, for which imipramine, desipramine, and nortriptyline appear to be effective, even in patients responding poorly to or who are intolerant of the stimulants (e.g., methylphenidate). Newer NE selective reuptake inhibitors also may be useful in this disorder; atomoxetine is approved for this application. Utility of SSRIs in this syndrome is not established, and bupropion, despite its similarity to stimulants, appears to have limited efficacy.

Antidepressants tend to provide a more sustained and continuous improvement of the symptoms of attention-deficit/hyperactivity disorder than do the stimulants and do not induce tics or other abnormal movements sometimes associated with stimulants. Indeed, desipramine and nortriptyline may effectively treat tic disorders, either in association with the use of stimulants or in patients with both attention deficit disorder and Tourette's syndrome. Antidepressants also are leading choices in the treatment of severe anxiety disorders, including panic disorder with agoraphobia, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder, as well as for the common comorbidity of anxiety in depressive illness. Antidepressants, especially SSRIs, also are employed in the management of posttraumatic stress disorder, which is marked by anxiety, startle, painful recollection of the traumatic events, and disturbed sleep. Initially, anxious patients often tolerate nonsedating antidepressants poorly (Table 17-1), requiring slowly increased doses. Their beneficial actions typically are delayed for several weeks in anxiety disorders, just as they are in major depression.

For panic disorder, tricyclic antidepressants and MAO inhibitors, as well as high-potency benzodiazepines (notably alprazolam, clonazepam, and lorazepam) (see Chapter 16), are effective in blocking the autonomic expression of panic itself, thereby facilitating a comprehensive rehabilitation program. Imipramine and phenelzine are well-studied antidepressants for panic disorder. SSRIs also may be effective, but b adrenergic receptor antagonists, buspirone, and low-potency benzodiazepines usually are not, and bupropion can worsen anxiety.

SSRIs are agents of choice in obsessive-compulsive disorder and in the syndromes of impulse dyscontrol or obsessive preoccupations (e.g., compulsive gambling, trichotillomania, bulimia, but usually not anorexia nervosa and body dysmorphic disorder). Despite their limited benefits, SSRIs offer an important advance in the medical treatment of these often chronic and sometimes incapacitating disorders. The effectiveness of pharmacological treatment for these disorders is greatly enhanced by use of behavioral treatments.

Several psychosomatic disorders may respond at least partly to treatment with tricyclic antide-pressants, MAO inhibitors, or SSRIs; among these are chronic pain disorders, including diabetic and other peripheral neuropathic syndromes (for which tertiary-amine tricyclics probably are superior to fluoxetine, and both duloxetine and venlafaxine also may be effective); fibromyalgia; peptic ulcer and irritable bowel syndrome; hot flashes of menopause; chronic fatigue; cataplexy; tics; migraine; and sleep apnea. These disorders may have some psychobiological relationship to mood or anxiety disorders.

For a complete Bibliographical listing see Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., or Goodman & Gilman Online at www.accessmedicine.com.

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