Clinical Evidence: A Publication of BMJ Publishing Group

Generalized Anxiety Disorder



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Am Fam Physician. 2003 Jan 1;67(1):135-138.

Questions Addressed

  • What are the effects of treatments?

Summary of Interventions

Beneficial Likely to be beneficial Trade off Unknown effectiveness

Cognitive therapy

Buspirone Certain antidepressants (paroxetine, imipramine, trazodone, opipramol, venlafaxine)

Benzodiazepines Kava

Applied relaxation

Hydroxyzine

Abecarnil

Antipsychotic drugs

Beta blockers

Summary of Interventions

View Table

Summary of Interventions

Beneficial Likely to be beneficial Trade off Unknown effectiveness

Cognitive therapy

Buspirone Certain antidepressants (paroxetine, imipramine, trazodone, opipramol, venlafaxine)

Benzodiazepines Kava

Applied relaxation

Hydroxyzine

Abecarnil

Antipsychotic drugs

Beta blockers

Definition

Generalized anxiety disorder (GAD) is defined as excessive worry and tension about everyday events and problems, on most days, for at least six months to the point where the person experiences distress or has marked difficulty in performing day-to-day tasks.1 It may be characterized by the following symptoms and signs: increased motor tension (fatigability, trembling, restlessness, and muscle tension); autonomic hyperactivity (shortness of breath, rapid heart rate, dry mouth, cold hands, and dizziness); and increased vigilance and scanning (feeling keyed up, increased startling, and impaired concentration), but not panic attacks.1 One non-systematic review of epidemiologic and clinical studies found marked reduction of quality of life and psychosocial functioning in people with anxiety disorders (including GAD).2 It also found that (using the Composite Diagnostic International Instrument) people with GAD have low overall life satisfaction and some impairment in ability to fulfill roles, social tasks, or both.2

Incidence/Prevalence

Assessment of the incidence and prevalence of GAD is difficult, because a large proportion of people with GAD have a comorbid diagnosis. One nonsystematic review identified the U.S. National Comorbidity Survey, which found that more than 90 percent of people diagnosed with GAD had a comorbid diagnosis, including dysthymia (22 percent), depression (39 to 69 percent), somatization, other anxiety disorders, bipolar disorder, or substance abuse.3 The reliability of the measures used to diagnose GAD in epidemiologic studies is unsatisfactory.4,5 One U.S. study, with explicit diagnostic criteria (DSM-III-R), estimated that 5 percent of people will develop GAD at some time during their lives.5 A recent cohort study of people with depressive and anxiety disorders found that 49 percent of people initially diagnosed with GAD retained this diagnosis after two years.6 One nonsystematic review found that the incidence of GAD in men is only one half the incidence in women.7 One nonsystematic review of seven epidemiologic studies found reduced prevalence of anxiety disorders in older people.8 Another nonsystematic review of 20 observational studies in younger and older adults suggested that the autonomic arousal to stressful tasks is decreased in older people, and that older people become accustomed to stressful tasks more quickly than younger people.9

Etiology/Risk Factors

One community study and a clinical study have found that GAD is associated with an increase in the number of minor stressors, independent of demographic factors,10 but this finding was common in people with other diagnoses in the clinical population.6 One non-systematic review (five case control studies) of psychologic sequelae to civilian trauma found that rates of GAD reported in four of the five studies were increased significantly compared with a control population (rate ratio: 3.3; 95 percent confidence interval [CI]: 2.0 to 5.5).11 One systematic review of cross-sectional studies found that bullying (or peer victimization) was associated with a significant increase in the incidence of GAD (effect size: 0.21).12 One systematic review (search date not stated) of the genetic epidemiology of anxiety disorders(including GAD) identified two family studies and three twin studies.13 The family studies (45 index cases; 225 first-degree relatives) found a significant association between GAD in the index cases and in their first-degree relatives (odds ratio [OR]: 6.1; 95 percent CI: 2.5 to 14.9). The twin studies (13,305 people) estimated that 31.6 percent (95 percent CI: 24 to 39 percent) of the variance to liability to GAD was explained by genetic factors.13

Prognosis

GAD often begins before or during young adulthood and can be a lifelong problem.14 Spontaneous remission is rare.

Clinical Aims

To reduce anxiety; to minimize disruption of day-to-day functioning; and to improve quality of life, with minimum adverse effects.

Clinical Outcomes

Severity of symptoms and effects on quality of life, as measured by symptom scores: usually the Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory, or Clinical Global Impression Symptom Scores. Where numbers needed to treat are given, these represent the number of people requiring treatment within a given time period (usually six to 12 weeks) for one additional person to achieve a certain improvement in symptom score. The method for obtaining numbers needed to treat was not standardized across studies. Some used a reduction by, for example, 20 points in the HAM-A as a response, others defined a response as a reduction, for example, by 50 percent of the premorbid score. We have not attempted to standardize methods, but instead have used the response rates reported in each study to calculate numbers needed to treat. Similarly, we have calculated numbers needed to harm from original trial data.

Definition

Generalized anxiety disorder (GAD) is defined as excessive worry and tension about everyday events and problems, on most days, for at least six months to the point where the person experiences distress or has marked difficulty in performing day-to-day tasks.1 It may be characterized by the following symptoms and signs: increased motor tension (fatigability, trembling, restlessness, and muscle tension); autonomic hyperactivity (shortness of breath, rapid heart rate, dry mouth, cold hands, and dizziness); and increased vigilance and scanning (feeling keyed up, increased startling, and impaired concentration), but not panic attacks.1 One non-systematic review of epidemiologic and clinical studies found marked reduction of quality of life and psychosocial functioning in people with anxiety disorders (including GAD).2 It also found that (using the Composite Diagnostic International Instrument) people with GAD have low overall life satisfaction and some impairment in ability to fulfill roles, social tasks, or both.2

Incidence/Prevalence

Assessment of the incidence and prevalence of GAD is difficult, because a large proportion of people with GAD have a comorbid diagnosis. One nonsystematic review identified the U.S. National Comorbidity Survey, which found that more than 90 percent of people diagnosed with GAD had a comorbid diagnosis, including dysthymia (22 percent), depression (39 to 69 percent), somatization, other anxiety disorders, bipolar disorder, or substance abuse.3 The reliability of the measures used to diagnose GAD in epidemiologic studies is unsatisfactory.4,5 One U.S. study, with explicit diagnostic criteria (DSM-III-R), estimated that 5 percent of people will develop GAD at some time during their lives.5 A recent cohort study of people with depressive and anxiety disorders found that 49 percent of people initially diagnosed with GAD retained this diagnosis after two years.6 One nonsystematic review found that the incidence of GAD in men is only one half the incidence in women.7 One nonsystematic review of seven epidemiologic studies found reduced prevalence of anxiety disorders in older people.8 Another nonsystematic review of 20 observational studies in younger and older adults suggested that the autonomic arousal to stressful tasks is decreased in older people, and that older people become accustomed to stressful tasks more quickly than younger people.9

Etiology/Risk Factors

One community study and a clinical study have found that GAD is associated with an increase in the number of minor stressors, independent of demographic factors,10 but this finding was common in people with other diagnoses in the clinical population.6 One non-systematic review (five case control studies) of psychologic sequelae to civilian trauma found that rates of GAD reported in four of the five studies were increased significantly compared with a control population (rate ratio: 3.3; 95 percent confidence interval [CI]: 2.0 to 5.5).11 One systematic review of cross-sectional studies found that bullying (or peer victimization) was associated with a significant increase in the incidence of GAD (effect size: 0.21).12 One systematic review (search date not stated) of the genetic epidemiology of anxiety disorders(including GAD) identified two family studies and three twin studies.13 The family studies (45 index cases; 225 first-degree relatives) found a significant association between GAD in the index cases and in their first-degree relatives (odds ratio [OR]: 6.1; 95 percent CI: 2.5 to 14.9). The twin studies (13,305 people) estimated that 31.6 percent (95 percent CI: 24 to 39 percent) of the variance to liability to GAD was explained by genetic factors.13

Prognosis

GAD often begins before or during young adulthood and can be a lifelong problem.14 Spontaneous remission is rare.

Clinical Aims

To reduce anxiety; to minimize disruption of day-to-day functioning; and to improve quality of life, with minimum adverse effects.

Clinical Outcomes

Severity of symptoms and effects on quality of life, as measured by symptom scores: usually the Hamilton Anxiety Scale (HAM-A), State-Trait Anxiety Inventory, or Clinical Global Impression Symptom Scores. Where numbers needed to treat are given, these represent the number of people requiring treatment within a given time period (usually six to 12 weeks) for one additional person to achieve a certain improvement in symptom score. The method for obtaining numbers needed to treat was not standardized across studies. Some used a reduction by, for example, 20 points in the HAM-A as a response, others defined a response as a reduction, for example, by 50 percent of the premorbid score. We have not attempted to standardize methods, but instead have used the response rates reported in each study to calculate numbers needed to treat. Similarly, we have calculated numbers needed to harm from original trial data.

Evidence-Based Medicine Findings

SEARCH DATE:CLINICAL EVIDENCE UPDATE SEARCH AND APPRAISAL FEBRUARY 2002

Evidence-Based Medicine Findings

SEARCH DATE:CLINICAL EVIDENCE UPDATE SEARCH AND APPRAISAL FEBRUARY 2002

Cognitive Therapy

Two systematic reviews and one nonsystematic review have found that cognitive behavior therapy, using a combination of interventions such as exposure, relaxation, and cognitive restructuring, improves anxiety and depression over four to 12 weeks more than remaining on a waiting list (no treatment), anxiety management training alone, relaxation training alone, or nondirective psychotherapy. One systematic review found limited evidence (by making indirect comparisons of treatments across different randomized controlled trials [RCTs]) that more people given individual cognitive therapy maintained recovery after six months than those given nondirective treatment, group cognitive therapy, group behavior therapy, individual behavior therapy, or analytic psychotherapy, but that fewer people maintained recovery after six months with cognitive therapy versus applied relaxation. One subsequent RCT found no significant difference in symptoms at 13 weeks with cognitive therapy versus applied relaxation. Another subsequent RCT in people older than 55 years with a variety of anxiety disorders found that cognitive behavior therapy versus supportive counseling significantly improved symptoms of anxiety over 12 months, but found no significant difference in symptoms of depression.

Applied Relaxation

We found no RCTs of applied relaxation versus placebo or no treatment. One systematic review found limited evidence, by making indirect comparisons of treatments across different RCTs, that more people given applied relaxation maintained recovery after six months than those given individual cognitive therapy, nondirective treatment, group cognitive therapy, group behavior therapy, individual behavior therapy, or analytic psychotherapy. One subsequent RCT found no significant difference in symptoms at 13 weeks with applied relaxation versus cognitive behavior therapy.

Benzodiazepines

One systematic review and one subsequent RCT found limited evidence that benzodiazepines versus placebo reduced symptoms over two to nine weeks. However, RCTs and observational studies found that benzodiazepines increased the risk of dependence, sedation, industrial accidents, and road traffic accidents. One nonsystematic review found that, if used in late pregnancy or while breast feeding, benzodiazepines may cause adverse effects in neonates. Limited evidence from RCTs found no significant difference in symptoms over six to eight weeks with benzodiazepines versus buspirone, abecarnil, or antidepressants. One systematic review of poor quality RCTs found insufficient evidence about the effects of long-term treatment with benzodiazepines.

Buspirone

RCTs have found that buspirone versus placebo significantly improves symptoms over four to nine weeks. Limited evidence from RCTs found no significant difference in symptoms over six to eight weeks with buspirone versus antidepressants or hydroxyzine.

Hydroxyzine

One RCT identified by a nonsystematic review found that hydroxyzine versus placebo significantly improved symptoms of anxiety after four weeks. Another RCT identified by the review found no significant difference in the proportion of people with improved symptoms of anxiety at 35 days with hydroxyzine versus placebo or buspirone.

Abecarnil

One RCT found no significant difference in symptoms at six weeks with abecarnil versus placebo or versus diazepam. One smaller RCT found limited evidence that low-dose abecarnil versus placebo significantly improved symptoms.

Antidepressants

RCTs have found that imipramine, opipramol, paroxe-tine, trazodone, or venlafaxine versus placebo significantly improved symptoms over four to eight weeks, and that they are not significantly different from each other. RCTs and observational studies have found that antidepressants are associated with sedation, dizziness, nausea, falls, and sexual dysfunction. Limited evidence from RCTs found no significant difference in symptoms over eight weeks with antidepressants versus benzodiazepines or buspirone. We found no systematic review or RCTs assessing sedating tricyclic antidepressants in people with GAD.

Antipsychotic Drugs

One RCT found that trifluoperazine versus placebo significantly reduced anxiety after four weeks, but caused more drowsiness, extrapyramidal reactions, and other movement disorders.

Beta Blockers

We found no RCTs assessing use of beta blockers in people with GAD.

Kava

One systematic review in people with anxiety disorders, including GAD, found that kava versus placebo significantly reduced symptoms of anxiety over four weeks. Observational evidence suggests that kava may be associated with hepatotoxicity.

Both authors have received funding from Eli Lilly.

Adapted with permission from Gale CK, Oakley-Browne M. Generalised anxiety disorder. Clin Evid 2002;8:974–90.

editor's note: Abecarnil and opipramol are not available in the United States.

 

REFERENCES

1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Association, 1994.

2. Mendlowicz MV, Stein MB. Quality of life in individuals with anxiety disorders. Am J Psychiatry. 2000;157:669–82.

3. Stein D. Comorbidity in generalised anxiety disorder: impact and implications. J Clin Psychiatry. 2001;62(suppl 11):29–34. (review).

4. Judd LL, Kessler RC, Paulus MP, et al. Comorbidity as a fundamental feature of generalised anxiety disorders: results from the national comorbidity study (NCS). Acta Psychiatry Scand. 1998;98(suppl 393):6–11.

5. Andrews G, Peters L, Guzman AM, et al. A comparison of two structured diagnostic interviews: CIDI and SCAN. Aust N Z J Psychiatry. 1995;29:124–32.

6. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States: results from the national comorbidity survey. Arch Gen Psychiatry. 1994;51:8–19.

7. Seivewright N, Tyrer P, Ferguson B, et al. Longitudinal study of the influence of life events and personality status on diagnostic change in three neurotic disorders. Depression Anx. 2000;11:105–13.

8. Pigott T. Gender differences in the epidemiology and treatment of anxiety disorders. J Clin Psychiatry. 1999;60(suppl 18):15–8.

9. Jorm AF. Does old age reduce the risk of anxiety and depression? A review of epidemiological studies across the adult life span. Psychol Med. 2000;30:11–22.

10. Lau AW, Edelstein BA, Larkin KT. Psychophysiological arousal in older adults: a critical review. Clin Psychol Rev. 2001;21:609–30. (review).

11. Brantley PJ, Mehan DJ Jr, Ames SC, et al. Minor stressors and generalised anxiety disorders among low income patients attending primary care clinics. J Nerv Ment Dis. 1999;187:435–40.

12. Brown ES, Fulton MK, Wilkeson A, Petty F. The psychiatric sequelae of civilian trauma. Comp Psychiatry. 2000;41:19–23.

13. Hawker DS, Boulton MJ. Twenty years' research on peer victimisation and psychosocial maladjustment: a meta-analytic review of cross-sectional studies. J Child Psychol Psychiatr. 2000;41:441–5.

14. Hettema JM, Neale MC, Kendler KS. A review and meta-analysis of the genetic epidemiology of anxiety disorders. Am J Psychiatry. 2001;158:1568–78. Search date not stated; primary source Medline.

This is one in a series of chapters excerpted from Clinical Evidence , published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence is published in print twice a year and is updated monthly online. Each topic is revised every eight months, and users should view the most up-to-date version at www.clinicalevidence.com. This series is part of the AFP 's CME. See “Clinical Quiz” on page 29.


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