Generalized anxiety disorder. (Feature CME Topic: Generalized Anxiety Disorder).

Abstract

Anxiety is a part of daily life. While mild levels of anxiety can be positive, moderate to severe levels can cause intense distress. When anxiety interferes with a person's ability to function, it warrants treatment. Generalized anxiety disorder (GAD) is a chronic disabling condition characterized by at least 6 months of frequent worries and three of the following symptoms: fatigue, restlessness, poor concentration, irritability, muscle tension, and unsatisfying sleep. The primary treatment for anxiety is pharmacotherapy. Medication prescribed for anxiety has shifted from exclusive benzodiazepine therapy to a combination of benzodiazepine and antidepressant drugs. The principal disadvantages of benzodiazepines are their long-term use with associated physical dependence, tolerance, and withdrawal symptoms. Several reports support the serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitors for the treatment of anxiety disorders.

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Anxiety is a common experience and part of everyday life. It is an aspect of both emotional and physical change. At mild levels, anxiety is considered "normal" and even a positive motivator for individuals to adapt and cope with stress. (1) Mild anxiety sharpens the senses and expands the perceptual field, preparing us for action while learning and problem-solving skills are enhanced. Moderate levels of anxiety, however, decrease the perceptual field. Sight, hearing, touch, taste, and smell are limited and the ability to think is impaired. Problem solving and the ability to mobilize resources can be hindered. Severe levels of anxiety constrict the perceptual field so that an individual's focus is limited to one specific detail. Completing a task or processing new information is compromised, and behavior and attention are directed toward the anxiety. Communication with a severely anxious person must be brief, simple, and direct. At panic level, the perceptual field is so diminished that people no longer effect ively interpret outside stimuli. Communication and daily living activities are dysfunctional and self-absorbed. Feelings of anger, fear, and helplessness may emerge explosively and are directed toward self or others in a fight-or-flight reaction. It is extremely difficult to gather information from or impart it to a person experiencing severe anxiety.

In clinical practice, anxiety is one of the most prevalent causes of health care provider visits. Anxiety occurs when individuals perceive threats to biologic or ego (psychological) integrity. (2) Some measure of anxiety can be expected as a temporary response to stress, such as when a patient waits for medical test results; but when anxiety becomes so severe that it interferes with one's ability to function in daily life or is inappropriately triggered, it is considered pathologic and warrants treatment.2 Anxiety is experienced as an unpleasant and unjustified sense of apprehension, often accompanied by autonomic arousal and somatic manifestations. It is unattached to a clearly identifiable stimulus, unlike an adjustment disorder with stress. It is an alarm that signals impending danger and warns us to prepare for action. Generalized anxiety disorder (GAD) is one of several anxiety disorders that include agoraphobia and other specific phobias, obsessive-compulsive disorder, panic disorder, posttraumatic str ess disorder, and social anxiety disorder. (3) This article defines GAD and explores treatment options.

Epidemiology

Lifetime prevalence of GAD occurs in approximately 5% of the general population and 10% of women older than 39 years of age. (4) Prevalence for GAD increases exponentially with age and is correlated with unemployment or chronic medical illnesses. (4) Diagnosis of GAD is generally uncommon before the age of 25. (5) In one study of adult primary care patients, 3.7% had GAD and 6.6% experienced subthreshold anxiety symptomatology. (6) Half of those with anxiety symptoms met full criteria for another mental disorder. The distinction between threshold symptoms, subthreshold symptoms, and comorbid symptoms may cause diagnostic difficulties.

Diagnosis

GAD is a chronic disabling condition characterized by frequent worries, somatic symptoms, and physical illnesses. The criteria for diagnosis include 6 months (3) of symptom duration with prominent worrying and significant distress or impairment. In addition, three of the following six symptoms should be present on most days: fatigue, restlessness, poor concentration, irritability, muscle tension, and unsatisfying sleep.

A number of medical conditions can present with anxiety (Table 1) and a variety of medications have anxiety or nervousness as side effects (Table 2).

Clinical Features

Anxiety presents in multiple domains with insomnia and somatic concerns as the most frequently reported symptoms. Common physical symptoms include increased heart rate, chest pain, palpitations, dyspnea, and diaphoresis. Other physiologic symptoms such as dizziness, urinary frequency, nausea, and muscle tension can also occur. Uncontrollable worry and feelings of apprehension or dread may accompany physical symptoms. Cognitive symptoms may include confusion, perceptual distortion, difficulty concentrating, and an inability to make decisions. Behavioral symptoms manifest as restlessness, agitation, change in speech patterns, and hypervigilance. Crying, irritability, hostility, and uncooperativeness are affective components of intense anxiety. People experiencing severe anxiety can be at increased risk for suicide. It is important to ask highly anxious individuals about suicidal and/or homicidal ideation.

Several characteristics can be used to distinguish GAD from nonpathologic anxiety. (3) Intolerance of uncertainty is a key diagnostic feature. (7) With GAD, worry is excessive and interferes with daily functioning. Normally, a person can put a particular apprehension into a manageable perspective and can determine a course of action to deal with the concern. With GAD, worries are generally widespread, intense, more disturbing, and can occur without any identifiable trigger. The duration is long-standing and can involve multiple areas of the person's life.

Neurobiology 

Neurobiological mechanisms in GAD are not clearly understood and individual biologic reports do not provide a sufficiently coherent pathophysiological framework. These findings are summarized as follows:

GAD patients may have an abnormal response to stress. For example, although baseline cerebral blood flow is normal, after psychological stress, cerebral blood flow variations are less than seen in controls. (8) Other findings include hyperactive brain circuits (indicated by increased metabolic activity in the thalamus) and hypervigilance. (8)

Rather than implicating a single neurotransmitter or region in the brain, the hypothesis of multiple neurotransmitter involvement across diverse regions of the central nervous system has been implicated in many psychiatric disorders. (9) For example, a dysregulated benzodiazepine receptor function has been described in GAD. (10) The N-methyl-D-aspartate/ glutamate (NMDA) receptor is implicated in the acquisition of conditioned fear response and fear-induced startle. (11) Supersensitivity of postsynaptic cholecystokinin neurons is thought to be present in most anxiety disorders. (12)

Abnormalities in central corticotropin-releasing factor neuronal functioning have been identified in several anxiety disorders, particularly posttraumatic stress disorder, with consequent adverse effects on the hypothalamic-pituitary-adrenal axis. (13) Such alterations may reflect changes in stress-related neurotransmitter systems and disturb arousal mechanisms.

Sleep is disturbed in GAD as well as in depression. Rapid eye movement (REM) latency and REM as a percentage of total sleep time are normal in GAD but increased in depression. (14) Total sleep time and sleep efficiency are reduced in both (15,16)

The sequence of symptoms resulting in sleep problems is suggested as follows: GAD hypervigilance and hyperarousal lead to insomnia which causes sleep deficiency and diurnal tiredness. (15)

Ninety percent of patients with a diagnosis of one or several anxiety disorders have a section on chromosome 15 duplicated. (17) This section, DUP25, is associated with the control of proteins responsible for interneuron communication in the fear response. When the production of a single protein is flawed, the net result can be an inability to shut down fear or panic reactions or there may be an exaggerated reaction to stress.

Differential Diagnosis

GAD is differentiated from panic disorder in that the excessive worry is not restricted to a panic attack. (3) In both, symptoms are severe and incapacitating but panic attacks are brief, intense episodes that peak quickly (usually in 10 minutes or less) and then dissipate. (3) By contrast, the symptoms of generalized anxiety disorder are lower in intensity and longer in duration.

Several medical conditions and medications can produce anxiety. Hypoglycemia, cardiac disorders, or conditions that impair airflow are commonly accompanied by anxiety. Diagnosis and treatment of the underlying medical illness alleviates the anxiety unless other factors contribute to apprehension.

Social phobia is manifested by a persistent fear of social situations and/or performance in public settings. Avoidance behavior is very typical for this condition but unusual in generalized anxiety. Individuals with free-floating anxiety may exhibit symptoms in social situations but, if they do not meet criteria for social phobia, they are more properly diagnosed with GAD.

Adjustment disorder with anxiety is characterized by a clear response to an identified stressful life event. Symptoms might be identical with those of generalized anxiety disorder, yet the duration is less than 6 months from the termination of the demanding incident.

Patients suffering from acute stress disorder or posttraumatic stress disorder experience memories of a traumatic event. This trauma would be extreme and frequently is life threatening.

Obsessive-compulsive disorder most often presents with checking or washing rituals. Such activities consume a great deal of time on a daily basis and interfere with necessary tasks or work.

Differentiating anxiety from depression is especially problematic since both can present simultaneously. A depressive disorder can be characterized by inability to experience pleasure, which is not typical for anxiety. Sadness and helplessness predominate in depressed people, while apprehension is greater for those with anxiety disorders. Affective and anxiety disorders coexist and cause symptoms in both areas. When depressive symptoms exist below a diagnostic threshold for a major depressive disorder, GAD should be considered. (18)

Comorbidity

A fundamental characteristic of GAD is comorbidity with other psychiatric conditions: (19) 62.4% major depression, 39.5% dysthymia, 37.6% alcoholism, 35.1% simple phobia, 34.4% social phobia, 27.6% drug abuse, and 23.5% panic disorder. (20) The majority (90.4%) of GAD patients have experienced comorbidity of GAD and another psychiatric condition. (20)

Comorbid GAD in elderly patients is associated with a more severe presentation of depressive illness and possible suicidal preoccupation. (21) The distinction between threshold, subthreshold, and comorbid symptoms may cause difficulties in accurately diagnosing patients presenting with anxiety.

Course and Prognosis

GAD is a chronic condition with the usual onset in women older than 35 and men older than 45 years of age. (5) It is characterized by a waxing and waning course. (4) Full and partial remission rates among lifetime cases approximate only one third of cases having a spontaneous remission. (20)

A review of anxiety disorders revealed an almost uniform picture of compromised quality of life and psychosocial dysfunction in afflicted individuals. (22) This report also cited significant impairment in subthreshold forms of anxiety disorders. Improvement in quality of life can be expected from effective treatment.

Remission criteria for GAD have been proposed as follows: a lack of functional impairment and a score on the Hamilton Anxiety Scale (HAM-A) of less than or equal to 7 to 10. (23) The HAM-A is helpful with diagnosing and tracking GAD and as an aid in decision-making issues such as intensifying, reducing, or changing treatments. The Anxiety Disorders Interview Schedule for DSM-IV: Child and Parent Versions (24) has been shown to be a reliable tool for diagnosing and monitoring children and adolescent patients.

Treatment

Psychotherapy. Personality dynamics, coping skills, interpersonal style, and situational stressors can affect the development of chronic anxiety. Psychotherapy is designed to address these issues. Cognitive-behavioral therapy (CBT) is a most useful psychotherapeutic technique in treating anxiety and has demonstrated effectiveness in at least 13 controlled treatment of GAD studies. (25) One investigation of inpatients with depression and anxiety who participated in CBT showed improvements in the quality of life, including work, education, leisure, housing, social relations, and psychological health. (26)

CBT is based on the theory that distress and impairment associated with anxiety are a product of an individual's belief system and interpretation of events. By changing negative thoughts, especially those that trigger discomfort, persons can change emotions, behaviors, and even physiologic processes.

The cognitive part of CBT emphasizes four steps: (25) (1) the patient examines perceptions around identified worries; (2) the patient and therapist review available evidence for and against the accuracy of these concepts; (3) more accurate cognitions are generated; and (4) the more that the patient can anticipate future worries or fears, the more effective they will be in reducing anxiety.

The behavioral component of this treatment has patients imagining stressful events that ordinarily initiate worry. They are told to pay attention to thoughts and feelings connected with the onset of worry. With continued practice, patients become increasingly aware of early cues to the anxiety process. Concurrently, relaxation training is taught using progressive muscle relaxation, slow breathing, and focusing attention on relaxing imagery. Patients then apply their learned relaxation techniques to future situations involving either worry cues, stressful events, or at random intervals to maintain their coping skills.

Therapy also focuses on avoidance of specific situations. Avoidance behavior often impairs social relations and daily functioning and can be targeted for psychotherapeutic intervention. Relaxation, visualization, and desensitization may help individuals learn to confront anxiety-provoking situations.

Relaxation techniques can effectively reduce anxiety. Progressive muscle relaxation, mentioned above, can reduce subjective feelings of anxiety and promote slower breathing with decreased muscle tension. The patient confronts anxiety-provoking situations first through visualization and later in reality. Rehearsal of these steps is necessary in order for patients to use this strategy in real-life situations. In the usual method, patients create a relaxed state and then imagine previous cues to anxiety-provoking situations. When patients begin to feel anxiety, relaxation can reduce tension. Regular practice is indispensable to establish these skills. A well-learned technique is especially helpful when combined with medication and cognitive therapy.

Biofeedback. Biofeedback has been successful in reducing anxiety levels in persons with GAD. These techniques use visual and auditory cues elicited from physiologic measures to teach patients how to control individual bodily responses to stress and anxiety. Primary care providers rarely have the time, training, or equipment to offer this technique. However, it is important to be aware of this resource as an option.

Pharmacotherapy. Pharmacotherapy is the most frequently used intervention for anxiety symptoms. Yet, anxiety disorders are often suboptimally managed. (27) Primary practitioners have the additional burden of recognizing anxiety disorders in patients presenting with other nonpsychological complaints. Recently, there has been a shift in medication choices for GAD, from exclusive benzodiazepine therapy to a combination of benzodiazepine and antidepressant drugs. (28) Principal disadvantages of the long-term use of benzodiazepines are physical dependence and withdrawal symptoms. Side effects with this class of drugs also include sedation, ataxia, and memory impairment. (29) Another potential adverse consequence of prolonged benzodiazepine intake is induction of a depressive disorder. (30) It is currently unclear if benzodiazepines fail to prevent depression in GAD patients or if they contribute to the development of depression when used on a long-term basis.

The tricyclic antidepressant drugs (TCAs) are probably as effective as benzodiazepines in the treatment of GAD. Imipramine and trazodone were compared with diazepam and placebo for somatic anxiety patients; all active agents were found better than placebo, with imipramine as the most effective drug. (31)

Several reports support the serotonin reuptake inhibitors (SSRIs) for treatment of GAD. (32) In one study, paroxetine, imipramine, and diazepam were compared in treating GAD. (33) Greater improvement in anxiety symptoms occurred with both paroxetine and imipramine than with diazepam. Other investigators studied fluvoxamine in older outpatients who have a variety of anxiety conditions. The data demonstrated reductions in anxiety, particularly in those with GAD. (34) These results, however, were confounded by the addition of adjunctive lorazepam, on an "as needed" basis. One important aspect of therapy with SSRIs is potential worsening of anxiety symptoms for 1 or 2 weeks after initiating medication. Patients need to be counseled about this possibility and encouraged to continue the medication through this period.

SSRIs are likewise favored for treatment of anxiety disorders in children.(35) Research has been conducted to evaluate the use of fluvoxamine at dosages of up to 300 mg per day in children ages 6 to 17 who were diagnosed with social phobia, separation anxiety, or GAD. (36) After 8 weeks of fluvoxamine therapy, anxiety was substantially reduced compared with placebo. Recommended starting dosages of the SSRIs for children younger than 12 years of age should be low, such as 5 to 10 mg fluoxetine or paroxetine, 25 mg sertraline, and 25 mg fluvoxamine. (35) An upward titration over time is then indicated, with maintenance dosages approximating the lower range of those used in adults.

The serotonin-norepinephrine reuptake inhibitor drug class was also studied for GAD. In a comparison study of venlafaxine XR or buspirone to placebo, venlafaxine XR produced statistically significant superiority over its competitors. (35) Two dosages were used, 75 and 150 mg/d venlafaxine XR, with both treatment groups being superior to placebo after the second week. (35) Positive results for venlafaxine XR in the treatment of GAD were demonstrated during a 6-month time period. (37) Advantages demonstrated from this placebo-controlled study included the convenient, once daily dosing schedule of venlafaxine XR and long-term efficacy. (37) Lower doses of venlafaxine have been recommended for children at 37.5 mg/d. (35)

Buspirone is a nonbenzodiazepine medication that appears to produce antianxiety effects through both presynaptic and postsynaptic serotonin-1A receptors. (38) In the dorsal raphe, it acts as a full agonist at presynaptic serotonin receptors, resulting in inhibition of neuronal activity and decreased serotonin synthesis. In the cortex and hippocampus, buspirone acts as a partial agonist at postsynaptic receptors. In the presence of a relative serotonin deficiency, buspirone acts as an agonist. When a serotonin surplus is present, it will act as an antagonist. Buspirone is void of anticonvulsant, muscle relaxant, psychomotor impairment, or sedative effects that are associated with benzodiazepines.

Benzodiazepines depress respiratory function while buspirone lacks this feature, making it a good choice for patients with coexisting anxiety and pulmonary disease. However, buspirone has a slow onset of antianxiety activity. Patients should try an adequate daily dose for approximately 8 weeks before assessing therapeutic outcomes. Patients should be educated regarding this delayed antianxiety result and convinced to allow buspirone an adequate trial period before claiming ineffectiveness.

Gabapentin, an anticonvulsant structurally resembling the neurotransmitter [gamma]-aminobutyric acid (GABA), has shown success in treating anxiety. It may act at NMDA and novel gabapentin receptors where it increases central levels of GABA and serotonin, with a sedating profile. (39,40) An additional advantage of this medication is the absence of dependence and withdrawal problems. (41)

Conclusions

Diagnosing and treating anxiety present challenges. Determining whether the anxiety is a primary diagnosis such as GAD, a comorbid disorder, an aspect of a medical problem, or a response to medication can be perplexing. Patients with GAD can be difficult to treat and sometimes test the clinician's patience. Frequent phone calls and office and emergency room visits can be exasperating for the provider when no medical cause can be found for the symptoms. Individuals experiencing severe anxiety suffer greatly. GAD can cause serious impairment in function, interfering with social, occupational, and educational fulfillment. With its chronic, non-remitting, and relapsing characteristics, GAD requires long-term therapy. Benzodiazepines offer good short-term relief; however, they are associated with cognitive and psychomotor impairment as well as abuse, dependence, tolerance, and withdrawal effects. Buspirone and antidepressant medications are other options; however, they are not free from problems. Psychotherapy is an effective intervention, often used in combination with a medication and relaxation. With proper treatment, considerable improvement can be expected.

Table 1

Medical conditions that can cause anxiety (a)

Disorder              Examples

Endocrine             Cushing's disease
                      Addison's disease
                      Hyperthyroidism
                      Premenstrual dysphoric disorder
                      Hypoglycemia
                      Hypercortisolism
                      Vitamin [B.sub.12] deficiency
Cardiovascular        Arrhythmias
                      Myocardial infarction
                      Angina
Gastrointestinal      Colitis
                      Peptic ulcer
Infections            HIV
                      Sepsis
                      Tuberculosis
Pulmonary             Asthma
                      Pneumothorax
                      Pulmonary embolus
                      COPD
Substance withdrawal  Ethanol, narcotics, nicotine,
Neurologic            sedative-hypnotics
                      CVA
                      Seizure disorders (temporal lobe)

(a)Note: Any condition that impact airflow is commonly accompanied by
anxiety. Adapted from: Lewis S. Anxiety, in Harkreader H (ed):
Fundamentals of Nursing: Caring and Clinical Judgment. Philadelphia,
W.B. Saunders Co., 2000, pp 1310-1328. (2) HIV, human immunodeficiency
virus: COPD, ehronic obstructive pulmonary disease: CVA, cardiovascular
accident.

Table 2

Medications that can cause anxiety

Category          Examples

Corticosteroids   Prednisone, methylprednisolone
Stimulants        Amphetamines, cocaine, methylphenidate
Bronchodilators   Albuterol, isoproterenol
Methylxanthines   Theophylline (in high doses)
Decongestants     Pseudoephedrine, phenyipropanolamine
Thyroid hormones  Levothyroxine, in excessive doses
Vasopressors      Epinephrine
Antidepressants   Bupropion, fluoxetine
Herbals           Ma huang, St. John's won, ginseng, guarana,
                    belladonna

Accepted October 28, 2002.

References

(1.) Rosenbaum JF, Pollack MH, Otto MW, Bernstein JG. Anxious patients, in Cassem NH, Stern TA, Rosenbaum JF, Jellinek MS (eds): Massachusetts General Hospital Handbook of General Psychiatry. St. Louis, Mosby-Year Book, 1997, ed 4, pp 173-210.

(2.) Lewis S. Anxiety, in Harkreader H (ed): Fundamentals of Nursing: Caring and Clinical Judgment. Philadelphia, W.B. Saunders Co., 2000, pp 1310-1328.

(3.) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC, American Psychiatric Association, 2000, ed 4 text rev, pp 436-476.

(4.) Wittchen HU, Hoyer J. Generalized anxiety disorder: Nature and course. J Clin Psychiatry 2001;62(Suppl 11): 15-19.

(5.) Carter RM, Wittchen HU, Phister H, Kessler RC. One-year prevalence of subthreshold and threshold DSM-IV generalized anxiety disorder in a nationally representative sample. Depress Anxiety 2001;13:78-88.

(6.) Olfson M, Broadhead WE, Weissmann MM, Leon AC, Farber L, Hoven C, et al. Subthreshold psychiatric symptoms in a primary care group practice. Arch Gen Psychiatry 1996;53:880-886.

(7.) Dugas MJ, Gagnon F, Ladouceur R, Freeston MH. Generalized anxiety disorder: A preliminary test of a conceptual model. Behav Res Ther 1998;36:215-226.

(8.) Nutt DJ. Neurobiological mechanisms in generalized anxiety disorder. J Clin Psychiatry 200l;62(Suppl 11):22-27.

(9.) Krystal JH, D'Souza DC, Sanacora G, Goddard AW, Charney DS. Current perspectives on the pathophysiology of schizophrenia, depression, and anxiety disorders. Med Clin North Am 2001;85:559-577.

(10.) Nutt DJ, Glue P, Lawson C, Wilson S. Flumazenil provocation of panic attacks: Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 1990;47:917-925.

(11.) Davis M, Rainnie D, Cassell M. Neurotransmission in the rat amygdala related to fear and anxiety. Trends Neurosci 1994;17:208-214.

(12.) Bradwejn J. CCK agonists and antagonists in clinical studies of panic and anxiety. Clin Neuropharmacal 1992;15:481A-482A.

(13.) Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, et al. Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 1997;154:624-629.

(14.) Reynolds CF III, Shaw DH, Newton TF, Coble PA, Kupfer DJ. EEG sleep in outpatients with generalized anxiety: A preliminary comparison with depressed outpatients. Psychiatry Res 1983;8:81-89.

(15.) Saletu-Zyhlarz G, Saletu B, Anderer P, Brandstatter N, Frey R, Gruber G, et al. Nonorganic insomnia in generalized anxiety disorder. 1. controlled studies on sleep, awakening and daytime vigilance utilizing polysomnography and EEG mapping. Neuropsychobiology 1997;36:117-129.

(16.) Thase ME, Simons AD, Reynolds CF III. Abnormal electroencephalographic sleep profiles in major depression: Association with response to cognitive behavior therapy. Arch Gen Psychiatry 1996;53:99-108.

(17.) Gratacos M, Nadal M, Martin-Santos R, Pujana MA, Gago J, Peral B, et al. A polymorphic genomic duplication on human chromosome 15 is a susceptibility factor for panic and phobic disorders. Cell 2001;106:367-379.

(18.) Rickels K, Rynn MA. What is generalized anxiety disorder? J Clin Psychiatry 2001;62(Suppl 11):4-12.

(19.) Judd LL, Kessler RC, Paulus MP, Zeller PV, Wittchen HU, Kunovac JL. Comorbidity as a fundamental feature of generalized anxiety disorders: Results from the National Comorbidity Study (NCS). Ada Psychiatr Scand Suppl 1998;393:6-11.

(20.) Wittehen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1994;51:355-364.

(21.) Lenze EJ, Mulsant BH, Shear MK, Schulberg HC, Dew MA, Begley AE, et al. Comorbid anxiety disorders in depressed elderly patients. Am J Psychiatry 2000;157:722-728.

(22.) Mendlowicz MV, Stein MB. Quality of life in individuals with anxiety disorders. Am J Psychiatry 2000;157:669-682.

(23.) Ballenger. Treatment of anxiety disorders to remission. J Clin Psychiatry 2001;62(Suppl 12):5-9.

(24.) Silverman WK, Saavedra LM, Pina AA. Test-retest reliability of anxiety symptoms and diagnosis with the Anxiety Disorders Interview Schedule for DSM-IV: Child and parent versions. J Am Acad Child Adolesc Psychiatry 2001;40:937-944.

(25.) Borkovec TD, Ruscio AM. Psychotherapy for generalized anxiety disorder. J Clin Psychiatry 2001;62(Suppl 11):37-45.

(26.) Lenz G, Dermal U. Quality of life in depression and anxiety disorders: An exploratory follow-up study after intensive inpatient cognitive behavior therapy. Psychopathology 2000;33:297-302.

(27.) Young AS, KIap R, Sherbourne CD, Wells KB. The quality of care for depressive and anxiety disorders in the United States. Arch Gen Psychiatry 2001;58:55-61.

(28.) Salzman C, Goldenberg I, Bruce SE, Keller MB. Pharmacologic treatment of anxiety disorders in 1989 versus 1996: Results from the Harvard/Brown anxiety disorders research program. J Clin Psychiatry 2001;62:149-152.

(29.) Davidson JRT. Pharmacotherapy of generalized anxiety disorder. J Clin Psychiatry 2001;2(Suppl 11):46 -50.

(30.) Lydiard RB, Laraia MT, Ballenger JC, Howell EF. Emergence of depressive symptoms in patients receiving alprazolam for panic disorder. Am J Psychiatry 1987;144:664-665.

(31.) Rickels K, Downing R, Schweizer E, Hassman H. Antidepressants for the treatment of generalized anxiety disorder: A placebo-controlled comparison of imipramine, trazodone and diazepam. Arch Gen Psychiatry 1993;50:884-895.

(32.) Davidson JR, DuPont RL, Hedges D, Haskins JT. Efficacy, safety, and tolerability of venlafaxine extended release and buspirone in outpatients with generalized anxiety disorder. J Clin Psychiatry 1999;60:528-535.

(33.) Rocca P, Fonzo V, Scotia M, Zanalda E, Ravizza L. Paroxetine efficacy in the treatment of generalized anxiety disorder. Ada Psychiatr Scand 1997;95:444-450.

(34.) Wylie ME, Miller MD, Shear MK, Little JT, Mulsant BH, Pollock BG, et al. Fluvoxamine pharmacotherapy of anxiety disorders in later life: Preliminary open-trial data. J Geriatr Psychiatry Neural 2000;13:43-48.

(35.) Williams T, Hodgman C. Medication for the management of anxiety disorders in children and adolescents. Pediatr Ann 2001;30:146-153.

(36.) The Research Unit on Pediatric Psychopharmacology Anxiety Study Group. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001;344:1279-1285, 1326-1327.

(37.) Gelenberg AJ, Lydiard RB, Rudolph RL, Aguiar L, Haskins JT, Salinas E. Efficacy of venlafaxine extended-release capsules in nondepressed outpatients with generalized anxiety disorder: A 6-month randomized controlled trial. JAMA 2000;283:3082-3088.

(38.) Eison AS, Eison MS. Serotonergic mechanisms in anxiety. Prag Neuropsychapharmocal Biol Psychiatry 1994;18:47-62.

(39.) Norton JW, Quarles E. Gabapentin and anxiety. Hasp Pharm 2001;36:843-845.

(40.) McEvoy GK. AHFS Drug Information 2001. Bethesda, MD, American Society of Health-System Pharmacists, 2001, pp 2094-2097.

(41.) Chouinard G, Beauclair L, Belanger MC. Gabapentin: Long-term antianxiety and hypnotic effects in psychiatric patients with comorbid anxiety-related disorders. Can J Psychiatry 1998;43:305.

RELATED ARTICLE: Key Points

* Mild levels of anxiety are considered "normal" and promote adaptation.

* When anxiety becomes so severe that it interferes with daily life or is inappropriately triggered, it is considered pathologic and warrants treatment.

* The criteria for the diagnosis of generalized anxiety disorder (GAD) include 6 months duration of symptoms with prominent worrying and significant distress or impairment.

* Three of the following six symptoms should be present on most days for a diagnosis of GAD: fatigue, restlessness, poor concentration, irritability, muscle tension, and unsatisfying sleep.

* Benzodiazepines offer good short-term relief; however, they are associated with cognitive and psychomotor impairment as well as a high degree of abuse, dependence, tolerance, and withdrawal effects. Antidepressants and buspirone are other options.

From the Mental Health and Behavioral Science and Pharmacy Service, Department of Veterans Affairs, and the Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY.

Reprint requests to Raymond Pary, MD, Veterans Affairs Medical Center, 800 Zorn Avenue #116, Louisville, KY 40206-1499. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9606-0581