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The EBMH Notebook summarises key messages about generalised anxiety disorder, sourced from: . For this review, Clinical Evidence Concise searched and appraised material published until June 2003.
Generalised anxiety disorder (GAD) is defined as excessive worry and tension about every day 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 characterised 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 epidemiological 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 people with GAD have low overall life satisfaction and some impairment in ability to fulfil roles, social tasks, or both.2
One overview of observational studies published in English found that the prevalence of GAD among adults in the community is 1.5–3.0%.3 It found that 3–5% of adults have had GAD in the past year and 4–7% have had GAD during their life. The US National Comorbidity Survey found that over 90% of people diagnosed with GAD had a comorbid diagnosis, including dysthymia (22%), depression (39–69%), somatisation, other anxiety disorders, bipolar disorder, or substance abuse.4 The Harvard Brown Anxiety Research Program also found that only 30/180 (17%) people had GAD alone.5 Subgroup analysis suggested that 46/122 (38%) of people with GAD had comorbid personality disorder.6 A systematic review of the comorbidity of eating disorders and anxiety disorders (search date 2001, two observational studies, 55 people) found a lifetime prevalence of GAD among people with anorexia nervosa of 24% in one study and 31% in the other.7 The lifetime prevalence of GAD in the control group of one of the studies (44 people) was 2%. The reliability of the measures used to diagnose GAD in epidemiological studies is unsatisfactory.8,9 One US study, with explicit diagnostic criteria (DSM-III-R), estimated that 5% of people will develop GAD at some time during their life.9 A recent cohort study of people with depressive and anxiety disorders found that 49% of people initially diagnosed with GAD retained this diagnosis over two years.10 The incidence of GAD in men is only half the incidence in women11 and is lower in older people.12 A non-systematic review (20 observational studies in younger and older adults) suggested that autonomic arousal to stressful tasks is decreased in older people, and that older people become accustomed to stressful tasks more quickly than younger people.13
Generalised anxiety disorder is believed to be associated with an increase in the number of minor stressors, independent of demographic factors,14,15 but this finding is also common in people with other diagnoses in the clinical population.10 One non-systematic review (five case control studies) of psychological sequelae to civilian trauma found that rates of GAD reported in four of the five studies were significantly increased compared with a control population (rate ratio 3.3, 95% CI 2.0 to 5.5).16 One systematic review (search date 1997) of cross sectional studies found that bullying (or peer victimisation) was associated with a significant increase in the incidence of GAD (effect size 0.21).17 Genetic factors are also implicated. One systematic review (search date not reported, two 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 (OR 6.1, 95% CI 2.5 to 14.9).18 The review also identified three twin studies (13 305 people), which estimated that 32% (95% CI 24% to 39%) of the variance to liability to GAD was explained by genetic factors.
One systematic review found that 25% of adults with GAD will be in full remission after two years, and 38% will have a remission after five years.3 The Harvard-Brown anxiety research program reported five year follow up of 167 people with GAD.19 In this period, the weighed probability for full remission was 38% and for at least partial remission was 47%: the probability of relapse from full remission was 27% and relapse from partial remission was 39%.
WHAT ARE THE EFFECTS OF TREATMENTS?
Likely to be beneficial
Randomised controlled trials (RCTs) have found that buspirone improves symptoms compared with placebo over 4–9 weeks. RCTs found no significant difference in symptoms over 6–8 weeks between buspirone and antidepressants, diazepam, or hydroxyzine, but the studies may have lacked power to detect clinically important differences among treatments.
Certain antidepressants (imipramine, opipramol, paroxetine, and venlafaxine)
Randomised controlled trials have found that antidepressants (imipramine, opipramol, paroxetine, and venlafaxine) improve symptoms over 4–28 weeks compared with placebo. RCTs found no significant difference among these antidepressants or between antidepressants and benzodiazepines or buspirone. RCTs and observational studies have found that antidepressants are associated with sedation, dizziness, nausea, falls, and sexual dysfunction.
Cognitive behavioural therapy
Two systematic reviews and two subsequent RCTs have found that cognitive behavioural therapy (using a combination of interventions, such as exposure, relaxation, and cognitive restructuring) improves anxiety and depression over 4–12 weeks compared with waiting list control, anxiety management alone, relaxation alone, or non-directive psychotherapy. Three subsequent RCTs, two in people aged ≥60 years, found no significant difference in symptoms at 13 weeks, six months, or 24 months between cognitive therapy and applied relaxation.
Three RCTs comparing hydroxyzine versus placebo found different results. Two RCTs found that, compared with placebo, hydroxyzine improved symptoms of anxiety at four or 12 weeks, but a third RCT found no significant difference in the proportion of people with improved symptoms of anxiety at five weeks. One of the RCTs found that hydroxyzine increased somnolence and headaches compared with placebo. One RCT found no significant difference between hydroxyzine and bromazepam in the proportion of people who responded after six weeks. Another RCT found no significant difference between hydroxyzine and buspirone in the proportion of people who responded after four weeks.
Trade off between benefits and harms
One systematic review and one subsequent RCT found that benzodiazepines reduced symptoms over 2–9 weeks compared with placebo. RCTs found no significant difference in symptoms over 3–8 weeks between alprazolam and bromazepam or mexazolam, or between benzodiazepines and buspirone, hydroxyzine, abecarnil, or antidepressants. RCTs and observational studies found that benzodiazepines increased the risk of dependence, sedation, industrial accidents, and road traffic accidents and that, if used in late pregnancy or while breast feeding, benzodiazepines may cause adverse effects in neonates. RCTs found no significant difference in symptoms over 3–8 weeks between alprazolam and bromazepam or mexazolam, or between benzodiazepines and buspirone, hydroxyzine, abecarnil, or antidepressants. One systematic review of poor quality RCTs provided insufficient evidence to assess long term treatment with benzodiazepines.
One systematic review in people with anxiety disorders, including generalised anxiety disorder, found that kava reduced symptoms of anxiety over 1–24 weeks compared with placebo. It is unclear whether results of the review are generalisable to people with generalised anxiety disorder. Observational evidence suggests that kava may be associated with hepatotoxicity.
One large RCT found that trifluoperazine reduced anxiety after four weeks compared with placebo, but caused more drowsiness, extrapyramidal reactions, and other movement disorders.
One RCT found limited evidence that low dose abecarnil improved symptoms compared with placebo. Another RCT found no significant difference in symptoms at six weeks between abecarnil and placebo or diazepam. Both RCTs found that abecarnil increased drowsiness compared with placebo.
We found no RCTs comparing applied relaxation versus placebo or no treatment. Three RCTs found no significant difference in symptoms at 13 weeks, six months, or 24 months between applied relaxation and cognitive behavioural therapy.
We found no RCTs on the effects of β blockers in people with generalised anxiety disorder.
CG has been paid by Eli Lilly, the manufacturer of Prozac (fluoxetine), and by Janssen to attend symposia. MOB has been paid by GlaxoSmithKline, the manufacturer of Aropax (paroxetine) for contributing to educational sessions for general practitioners. MOB has also been reimbursed by Pfizer for attending a conference.
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