Generalised anxiety disorder

Christopher K Gale; Jane Millichamp

. 2007 Nov 20;2007:1002.

Generalised anxiety disorder

Christopher K Gale ^1,^#, Jane Millichamp ^2,^#

PMCID: PMC2943796 PMID: 19450347

Key Points

Generalised anxiety disorder (GAD) is excessive worry and tension about everyday events, on most days, for at least 6 months, to the extent that there is distress or difficulty in performing day-to-day tasks. However, diagnosing GAD accurately can be difficult.

Up to one in twenty people may have GAD at any one time, and most have other health problems. Less than half of people have full remission after 5 years.
GAD may have a genetic component, and has also been linked to previous psychological or other trauma.

In adults:

CBT (including exposure, relaxation, and cognitive restructuring) improves anxiety and depression compared with waiting list control or treatment as usual.

It is unclear whether CBT is more effective than supportive therapy.

Various drug treatments, such as benzodiazepines, buspirone, hydroxyzine, antidepressants, and pregabalin may all reduce symptoms of anxiety in people with GAD, but they can have unpleasant adverse effects, and most studies have been short term.

Benzodiazepines increase the risk of dependence, sedation, and accidents, and can cause adverse effects in neonates if used during pregnancy.
Buspirone may be less effective if used in people who have recently been taking benzodiazepines.
Antidepressants (imipramine, paroxetine, sertraline, escitalopram, venlafaxine, and opipramol) have been shown to reduce symptoms compared with placebo, but antidepressants can cause a variety of adverse effects including sedation, dizziness, falls, nausea, and sexual dysfunction.
In general, comparisons between different antidepressants have shown similar effectiveness in reducing anxiety, although one study found limited evidence of an increased benefit with escitalopram compared with paroxetine.

Antipsychotic drugs may reduce anxiety in people who have not responded to other treatments, but these drugs may have serious adverse effects (e.g. drowsiness, movement disorders).

We don't know whether abecarnil reduces anxiety.

In children and adolescents:

CBT improves symptoms compared with waiting list control.

Most studies of CBT in children and adolescents have included other anxiety disorders. We found no studies in participants with GAD alone, or in children aged less than 6 years.

There is limited evidence regarding the efficacy of antidepressants for childhood GAD. SSRIs (fluvoxamine, fluoxetine, sertraline) have shown some promise, but antidepressants are associated with adverse effects such as abdominal pain and nausea, and other well documented adverse effects.

We found no evidence on the effects of applied relaxation, benzodiazepines, buspirone, hydroxyzine, abecarnil, pregabalin, or antipsychotics in children and adolescents.

About this condition

Definition

Generalised anxiety disorder (GAD) is defined as excessive worry and tension about every day events and problems, on most days, for at least 6 months, to the point where the person experiences distress or has marked difficulty in performing day-to-day tasks. 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 by panic attacks. One non-systematic review of epidemiological and clinical studies found marked reduction in quality of life and psychosocial functioning in people with anxiety disorders, including GAD. It also found that people with GAD had low overall life satisfaction, and some impairment in ability to fulfil roles, social tasks, or both.

Incidence/ Prevalence

The most recent community surveys have used a newer version of the Composite International Diagnostic Interview (CIDI) that allows direct comparisons between different surveys. One observational survey in Europe completed in 2003, which included people from Belgium, France, Germany, Italy, the Netherlands, and Spain, estimated the 12-month prevalence of GAD at 1.0% (0.5% males, 1.3% females).An observational survey in New Zealand (12,800 people) estimated the 12-month prevalence of GAD at 2.0%, 95% CI 1.7% to 2.3% (men: 1.4%, 95% CI 1.1% to 1.8%; women: 2.6%, 95% CI 2.2% to 3.1%). In this survey, people over the age of 65 years had a markedly lower 12-month prevalence of GAD (1.0%, 95% CI 0.6% to 1.5%). The lifetime prevalence of GAD was estimated to be 6.0%, 95% CI 5.5% to 6.6%. An observational survey in the UK in 2000 of people aged 16-74 years used the CIS-R,followed by a Schedules for Clinical Assessment in Neuropsychiatry [SCAN] interview of a stratified sample. The survey estimated that 4.7% of people had GAD (men: 4.6%; women: 4.8%). A survey of children and adolescents aged 5-16 years in the UK in 2004, which used a similar methodology, estimated that 0.7% had GAD (boys: 0.6%; girls: 0.8%). In the European survey of adults, 76% of those people who had more than one mental disorder for 12 months had GAD. Those people who had GAD were significantly more likely to have other mental disorders which included (odds ratio to have the disorder): major depression (OR 37.1, 95% CI 23.2 to 59.1), social phobia (OR 13.5, 95% CI 7.8 to 23.6), specific phobia (OR 7.4, 95% CI 4.6 to 12.0), post-traumatic stress disorder (OR 16.4, 95% CI 9.1 to 29.8), agoraphobia (OR 26.6, 95% CI 10.8 to 65.1), panic disorder (OR 21.8, 95% CI 11.5 to 41.2), and alcohol dependence (OR 18.9, 95% CI 4.8 to 74.4). Another observational survey in 2004 found that individuals with GAD were also more likely to have physical health problems.A non-systematic review (20 observational studies in younger and older adults) suggested that autonomic arousal to stressful tasks was decreased in older people, and that older people became accustomed to stressful tasks more quickly than younger people.

Aetiology/ Risk factors

GAD is believed to be associated with an increase in the number of minor life events, independent of demographic factors; however, this finding is also common in people with other diagnoses. One non-systematic review (5 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 (RR 3.3, 95% CI 2.0 to 5.5). 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, CI not reported). One systematic review (search date not reported, 2 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). One systematic review of twin and family studies (search date 2003, 23 twin studies, 12 family studies) found an association between GAD, other anxiety disorders, and depression, and postulated that a common genetic factor was implicated.

Prognosis

One systematic review found that 25% of adults with GAD will be in full remission after 2 years, and 38% will have a remission after 5 years. The Harvard-Brown anxiety research program reported 5-year follow-up of 167 people with GAD. During this period, the weighted probability for full remission was 38% and for at least partial remission was 47%; the probability of relapse from full remission was 27%, and of relapse from partial remission was 39%.

Aims of intervention

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

Outcomes

Severity of symptoms, social functioning, and effects on quality of life, as measured by symptom scores on continuous rating scales; adverse affects of treatments. Frequently-used rating scales include the Hamilton Anxiety Scale (HAM-A), Spielberger State-Trait Anxiety Inventory (STAI), and Clinical Global Impressions Scale (CGI). Other continuous scales include the Penn State Worry Questionnaire (PSWQ), Anxiety Status Inventory (ASI), and the GAD Severity Scale. Where numbers needed to treat are given, these represent the number of people requiring treatment within a given time period (usually 6-12 weeks) for one additional person to achieve a certain improvement in symptom score. The method for obtaining numbers needed to treat was not standardised across studies. Some RCTs defined a reduction by, for example, 20 points in the HAM-A as a clinical response; others defined a clinical response as a reduction by, for example, 50% of the pretreatment score. The authors have not attempted to standardise methods, but instead have used the response rates reported in each study to calculate numbers needed to treat.

Methods

BMJ Clinical Evidence search and appraisal March 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to March 2007, Embase 1980 to March 2007, PsycInfo 1967 to March 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for evaluation in this review were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Recent changes in diagnostic classification make it difficult to compare older studies versus more recent ones. In the earlier classification system (DSM-III-R), the diagnosis was made only in the absence of other psychiatric disorders. In current systems (DSM-IV and International Classification of Diseases 10 [ICD-10]), GAD can be diagnosed in the presence of any co-morbid condition.

Glossary

Analytical psychotherapy: A semi-structured therapy involving exploration of previous events in relation to an underlying theory around emotional states, generally based on one of the psychoanalytical theories.
Applied relaxation: A technique involving training in relaxation techniques and self-monitoring of symptoms without challenging beliefs.
Clinical Global Impressions Scale (CGI or CGIS): A clinician rated scale, usually from 0–4, with descriptions of severity at each point: 0 = no symptoms; 1 = very mild, subclinical symptoms; 2 = mild but clinical symptoms; 3 = moderate severity; and 4 = severe symptoms.
Cognitive behavioural therapy: Brief (20 sessions over 12–16 weeks) structured treatment incorporating elements of cognitive therapy and behavioural therapy. Covers a variety of techniques. Behavioural therapy is based on learning theory and concentrates on changing behaviour. Cognitive therapy is aimed at identifying anxiety associated thoughts and beliefs, changing over-monitoring of physical symptoms and minimising the catastrophising that characterises generalised anxiety disorder. This is combined with relaxation, exercise, and testing the validity of beliefs in real life situations. Cognitive restructuring involves systematic challenging of thought processes and underlying assumptions related to the symptoms. Exposure entails being confronted (through visualisation, image, or the stimulus) with an anxiogenic stimulus in a repetitive and prolonged manner. Relaxation involves practising techniques that lead to muscular or bodily relaxation. Systematic desensitisation is a type of exposure. Anxiety management training is a structured therapy involving education about anxiety, relaxation training, and exposure to anxiogenic stimuli; however, it does not include cognitive restructuring.
Hamilton Anxiety Scale (HAM-A): The HAM-A is a validated instrument consisting of 14 items scored on a 5-point scale, ranging from 0 (not present) to 4 (severe), to give a total score of between 0 and 56.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Contributor Information

Christopher K Gale, Department of Psychological Medicine, Dunedin Medical School, University of Otago, Dunedin, New Zealand.

Jane Millichamp, Department of Psychological Medicine, Dundedin School of Medicine, University of Otago, Dunedin, New Zealand.

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BMJ Clin Evid. 2007 Nov 20;2007:1002.

CBT in adults

Summary

Systematic reviews and additional RCTs found that CBT (using a combination of interventions, such as exposure, relaxation, and cognitive restructuring) improved anxiety and depression compared with waiting list control or treatment as usual, anxiety management alone, relaxation alone, or non-directive psychotherapy. One review found that CBT improved clinical response rates compared with behavioural therapy, although it found no significant difference between groups in anxiety symptoms. The review found no significant difference in clinical response rates between CBT and supportive therapy, although CBT improved anxiety symptoms compared with supportive therapy. However, in long-term follow-up, the rates of recovery from all psychotherapies became similar but superior to those of waiting list controls.

Benefits

We found four systematic reviews and and two additional RCTs comparing CBT versus waiting list control (no treatment) or versus other psychotherapies in people with generalised anxiety disorder (GAD) (see table 1 ). Many of the RCTs were small and were not analysed on an intention-to-treat basis.

Table 1.

Studies examining effects of CBT (see text).

Study design, ref	Population	Comparison	Outcome	Follow-up	Results

CBT v waiting list control or non-specific therapies

Systematic review (search date 1996)	13 RCTs, 722 people aged 18–60 years, 60% women	CBT (which involved, alone or in combination, cognitive restructuring, relaxation, exposure, and systematic desensitisation) v control (remaining on a waiting list, anxiety management alone, relaxation alone, and non-directive psychotherapy)	Anxiety Depression	4–12 weeks 4–12 weeks	Effect size: 0.70, 95% CI 0.57 to 0.83; absolute data not reported Effect size: 0.77, 95% CI 0.64 to 0.90; absolute data not reported

Systematic review (search date not reported)	5 RCTs, 313 people aged 18–60 years. Included three RCTs identified by the first review	CBT (including relaxation, cognitive therapy, behavioural therapy, and anxiety management training, alone or in combination) or analytical psychotherapy v waiting list control	Mean effect size for anxiety, treatment versus control Mean effect size for anxiety, treatment versus control	Post-treatment 12–18 months	5 RCTs, 0.9; 95% CI and P value not reported 1 RCT, 0.7%; 95% CI and P value not reported

Systematic review (search date 2006)	8 RCTs, 334 people	CBT compared with waiting list control or treatment as usual	Response rate measured by clinician-rated composite measure or structured diagnostic interviews		46% in cognitive therapy group responded v 14% in waiting list/treatment-as-usual group, RR 0.64, 95% CI 0.55 to 0.74
Systematic review (search date 2006).	10 RCTs	CBT was compared with waiting list control or a non-specific therapy (such as supportive therapy)	Anxiety symptoms: all trials used PSWQ		The pooled effect size for CBT versus control was 1.15 ( P less than 0.05)

CBT and anxiety management v psychodynamic therapy

Systematic review] (search date 2006)	1 RCT, 110 people.	Cognitive therapy and anxiety management compared with psychodynamic therapy	Response rate defined from STAI-I	After therapy; at six months	After therapy: 28% in combined group responded v 7% in psychodynamic group, RR 0.77, 95% CI 0.65 to 0.92; at six months: 39% of combined group responded v 23% with psychodynamic therapy, RR 0.79, 95% CI 0.62 to 1.01

CBT v supportive therapy

Systematic review (search date 2006)	Six RCTs, 332 people.	Cognitive therapy compared with supportive therapy	Response rate assessed through composite measure of anxiety severity (3 RCTs) and HAM-A (3 RCTs)	Post treatment	42% in cognitive therapy group responded v 28% with supportive therapy, RR 0.86, 95% CI 0.70 to 1.06

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BAI, Beck Anxiety Inventory; GAD, generalised anxiety disorder; HAM-A, Hamilton Anxiety Rating Scale; PSWQ, Penn State Worry Questionnaire; Ref, reference; STAI, Spielberger State-Trait Anxiety Inventory

CBT versus waiting list control or non-specific therapies:

The first systematic review (search date 1996, 13 RCTs, 722 people) found that CBT significantly improved symptoms over 4–12 weeks compared with control (waiting list, anxiety management alone, relaxation alone, or non-directive psychotherapy)(see table 1 ). The second systematic review (search date not reported, 5 RCTs, 313 people) found that CBT or analytical psychotherapy improved symptoms compared with waiting list control(see table 1 ).The third systematic review (search date 2006) included thirteen RCTs which compared cognitive-based therapies versus treatment as usual or waiting list control. Of those, eight studies (334 people) reported clinical response to treatment with CBT. The review found that, compared with control, CBT significantly increased clinical response (see table 1 ). Twelve included RCTs reported on anxiety symptom scores. The review found that CBT significantly improved mean anxiety symptom scores compared with control (12 RCTs, 330 people, SMD –1.00, 95% CI –1.24 to –0.77).A fourth systematic review (search date 2006) concentrating on symptoms of anxiety (as measured by the Penn State Worry Questionnaire) identified 10 RCTs where CBT was compared with a waiting list control or a non-specific therapy (such as supportive therapy). It reported pooled effect sizes and found a significant benefit with CBT (see table 1 ). The pooled effect size for CBT versus either supportive or no therapy was 1.15 (P less than 0.05; absoute numbers not reported). However, the review noted that the RCTs were heterogenous (age was a confounding factor), and reanalysed the data for younger (mean age 38 years) and older (mean age 68 years) adults (age range in each group not further defined). The pooled effect size was still significant for CBT compared with supportive or no therapy for both age groups (1.69 for younger adults and 0.82 for older adults; P less than 0.05 for either comparison).

CBT versus psycho-dynamic therapy:

One systematic review (search date 2006) included one RCT (110 people)(see table 1 ). After therapy, it found that cognitive therapy plus anxiety management significantly increased clinical response compared with analytical psychotherapy (clinical response: 28% with cognitive therapy plus anxiety management v 7% with analytical psychotherapy; RR 0.77, 95% CI 0.65 to 0.92). At six months, however, it found no significant difference in clinical response between groups (clinical response: 39% with cognitive therapy plus anxiety management v 23% with analytical psychotherapy; RR 0.79, 95% CI 0.62 to 1.01).

CBT versus supportive therapy:

One systematic review (search date 2006) included 6 RCTs comparing CBT versus supportive therapy (see table 1 ).The review found no significant difference in clinical response between CBT and supportive therapy at the end of treatment (6 RCTs, 332 people, RR 0.86, 95% CI 0.7 to 1.06), or between groups at six months (3 RCTs, 158 people, RR 0.79, 95% CI 0.59 to 1.06). In contrast, it found that, compared with supportive therapy, CBT significantly improved anxiety symptoms both post-treatment (6 RCTs, 235 people, SMD –0.40, 95% CI –0.66 to –0.14) and at six months (3 RCTs, 97 people, SMD –0.42, 95% CI –0.83 to –0.02).

Cognitive therapy versus behavioural therapy (including applied relaxation):

One systematic review (search date 2006) included 5 RCTs and pooled data (see table 1 ).Three included RCTs compared cognitive therapy versus applied relaxation; one included RCT compared combined relaxation plus cognitive restructuring, cognitive restructuring, and applied progressive muscle relaxation; and one included RCT compared cognitive therapy, analytic psychotherapy, and anxiety management training. The review found that cognitive therapy significantly improved response rates compared with behavioural therapy at the end of treatment (clinical response: 5 RCTs, 220 people, 50% with cognitive therapy v 31% with behavioural therapy, RR 0.70, 95% CI 0.56 to 0.87) and also at six months (clinical response: 2 RCTs, 105 people, 58% with cognitive therapy v 29% with behavioural therapy, RR 0.56, 95% CI 0.40 to 0.79). Four RCTs reported on anxiety symptom scores post treatment. The review found no significant difference in mean anxiety scores between cognitive and behavioural therapy, post treatment (4 RCTs, 131 people, SMD –0.06, 95% CI –0.40 to +0.30) or at six months (2 RCTs, 67 people, SMD –0.11, 95% CI –0.59 to +0.37).The review did not separately pool data on cognitive therapy versus applied relaxation alone. One included RCT (36 people) found no significant difference in clinical response between cognitive therapy and applied relaxation post treatment (RR 0.60, 95% CI 0.28 to 1.30). Another included RCT (45 people) found no significant difference in clinical response between cognitive therapy and applied relaxation post treatment (RR 0.80, 95% CI 0.51 to 1.26). A third included RCT (40 people) found a significant benefit in clinical response with cognitive therapy compared with applied relaxation post treatment (RR 0.29, 95% CI 0.11 to 0.72), but found no significant difference between groups at 6 months (RR 0.55, 95% CI 0.25 to 1.19).An additional RCT (76 people) found no significant difference in the proportion of people in each group who no longer met criteria for GAD imediately after treatment, and at 24 months, between cognitive therapy (with a behavioural component), cognitive therapy (without a behavioural component) and applied relaxation with visualisation.It also found no significant difference in six anxiety measures and two depression measures.

CBT versus non-specific therapy in benzodiazepine discontinuation:

We found one RCT (61 people with GAD who had used benzodiazepines for at least 12 months) which compared CBT plus medication tapering for benzodiazepine discontinuation versus non-specific psychological therapy (based on active listening) plus medication tapering. Both groups had twelve 90-minute sessions of therapy. The RCT found that, at the end of the treatment, CBT plus medication tapering significantly increased the proportion of people who had stopped benzodiazepines compared with non-specific psychological therapy plus medication tapering (74% of the cognitive group v 37% of the control group; P = 0.003). At 12 months' follow-up, the difference remained significant in favour of CBT compared with non-specific therapy (complete cessation of benzodiazepines: 65% of the cognitive group v 30% of the control group; P = 0.007).

Harms

The reviews and subsequent RCTs gave no information about adverse effects.

Comment

Another systematic review (search date 1998, 6 RCTs comparing cognitive therapy versus a variety of other psychological treatments, 404 people) did not compare treatments directly and was excluded from this review.

Substantive changes

CBT in adults Two systematic reviews and one RCTadded; benefits and harms data enhanced, categorisation unchanged (Beneficial).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Applied relaxation in adults

Summary

We found no RCTs comparing applied relaxation versus placebo or no treatment. Two RCTs included in a systematic review found no significant difference in clinical response post treatment between applied relaxation and CBT. Another RCT included in a systematic review found that cognitive therapy increased clinical response post treatment compared with applied relaxation, but found no significant difference between groups at 6 months. One additional RCT found no significant difference in anxiety and depression at 24 months between applied relaxation with visualisation, cognitive therapy (with a behavioural component), and cognitive therapy (without a behavioural component).

Benefits

Applied relaxation versus placebo or no treatment:

We found no systematic review or RCTs.

Applied relaxation versus other psychological treatments:

See benefits of CBT.

Harms

Applied relaxation versus other psychological treatments:

See harms of CBT.

Comment

We found one systematic review (search date 1998, 6 RCTs, 404 people) comparing applied relaxation versus a variety of other psychological treatments, which did not compare treatments directly (see comment on CBT).

Substantive changes

Applied relaxation in adults One systematic review comparing applied relaxation versus CBT added;benefits and harms data enhanced, categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Benzodiazepines in adults

Summary

Two systematic reviews 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. One RCT found no significant difference in anxiety scores at 4 weeks between lorazepam and pregabalin, whereas another RCT found that alprazolam was less effective than pregabalin at improving anxiety scores at 4 weeks. RCTs and observational studies found that benzodiazepines increased the risk of dependence, sedation, industrial accidents, and road traffic accidents. If used in late pregnancy or while breast feeding, benzodiazepines may cause adverse effects in neonates. One systematic review of poor-quality RCTs provided insufficient evidence to assess long-term treatment with benzodiazepines.

Benefits

Benzodiazepines versus placebo:

We found two systematic reviews (search date 1996, 17 RCTs, 2044 people;and search date 2002, 37 RCTs). The first review found that benzodiazepines significantly improved symptoms over 2–9 weeks compared with placebo (pooled mean effect size 0.70; CI not reported). In the second review, pooled results revealed that benzodiazepines were significantly more effective than placebo at improving anxiety.

Benzodiazepines versus each other:

We found two RCTs. The first RCT (121 people) compared sustained release alprazolam versus bromazepam. It found no significant difference in Hamilton Anxiety Scale scores or Clinical Global Impressions Scale (CGI) scores over 5 weeks between alprazolam and bromazepam (reported as non-significant, results presented graphically). The second RCT (64 people) compared mexazolam versus alprazolam, and found no significant difference in the proportion of people who had “highly improved” or “moderately improved” CGIS scores at 3 weeks (98% with “highly improved” v 87% with “moderately improved”; P greater than 0.05; absolute numbers presented graphically).

Long-term treatment:

We found one systematic review (search date 1998, 8 RCTs, any benzodiazepine medication, more than 2 months' duration). It found that the weak methods of the RCTs prevented firm conclusions being drawn.

Benzodiazepines versus buspirone:

See benefits of buspirone .

Benzodiazepines versus hydroxyzine:

See benefits of hydroxyzine.

Benzodiazepines versus abecarnil:

See benefits of abecarnil.

Benzodiazepines versus antidepressants:

See benefits of antidepressants.

Benzodiazepines versus pregabalin:

See benefits of pregabalin.

Harms

Benzodiazepines versus placebo:

The first review gave no information on harms. One RCT included in the second review found that, compared with placebo, both diazepam and abecarnil significantly increased drowsiness (52% with diazepam v 47% with abecarnil v 14% with placebo; P less than 0.05 for either drug v placebo) and dizziness (11% with diazepam v 16% with abecarnil v 3% with placebo; P less than 0.05 for either drug v placebo).

Dependence and sedation:

One non-systematic review of the harms of benzodiazepines found that rebound anxiety on withdrawal was reported in 15–30% of people. It also found that there was a high risk of substance abuse and dependence with benzodiazepines. One RCT identified by the first review found that diazepam increased rates of drowsiness (71% with diazepam v 13% with placebo; P = 0.001) and dizziness (29% with diazepam v 11% with placebo; P = 0.001) compared with placebo.

Memory:

Thirty-one people with agoraphobia/panic disorder in an RCT comparing alprazolam versus placebo for 8 weeks were reviewed after 3.5 years. Five people were still taking benzodiazepines and had significant impairment in memory tasks. There was no clear difference in memory performance between those who had been in the placebo group and those who had been given alprazolam but were no longer taking the drug.

Road traffic accidents:

We found one systematic review (search date 1997) examining the relationship between benzodiazepines and road traffic accidents. In the case control studies, the odds ratio for death or emergency medical treatment in those who had taken benzodiazepines compared with those who had not taken them was 1.45–2.40. The odds ratio increased with higher doses and more recent intake. In the police and emergency-ward studies, benzodiazepine use was a factor in 1–65% of accidents (usually 5–10%). In two studies in which people had blood alcohol concentrations under the legal limit, benzodiazepines were found in 43% and 65% of people. For drivers aged over 65 years, the risk of being involved in reported road traffic accidents was higher if they had taken longer-acting and larger quantities of benzodiazepines. These results are from case control studies and, consequently, subject to confounding.

Pregnancy and breast feeding:

One systematic review (search date 1997) of 23 case series and reports found no association between cleft lip and palate and benzodiazepines during the first trimester of pregnancy. However, case reports in one non-systematic review suggested that benzodiazepines taken in late pregnancy may be associated with neonatal hypotonia and withdrawal syndrome. Benzodiazepines are secreted in breast milk, and there have been reports of sedation and hypothermia in infants.

Other:

One non-systematic industry-funded review (8 RCTs) comparing benzodiazepines versus placebo or buspirone found that recent use of benzodiazepines limited the effectiveness of buspirone in people with generalised anxiety disorder.

Benzodiazepines versus buspirone:

See harms of buspirone.

Benzodiazepines versus hydroxyzine:

See harms of hydroxyzine.

Benzodiazepines versus abecarnil:

See harms of abecarnil.

Benzodiazepines versus antidepressants:

See harms of antidepressants.

Benzodiazepines versus pregabalin:

See harms of pregabalin.

Comment

All of the RCTs assessing benzodiazepines were short term (at most 12 weeks).

Substantive changes

Benzodiazepines in adults One systematic review comparing benzodiazepines versus buspirone added;benefits and harms data enhanced, categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Buspirone in adults

Summary

RCTs found that buspirone improved symptoms over 4–9 weeks compared with placebo. RCTs found no significant difference in symptoms over 6–8 weeks between buspirone and antidepressants (venlafaxine), diazepam, or hydroxyzine, but the studies might have lacked power to detect clinically important differences between treatments. Adverse effects associated with buspirone included increased nausea and somnolence.

Benefits

We found three systematic reviews (search date 1996, 9 RCTs;search date 2002, 12 RCTs;and search date 2005).

Buspirone versus placebo:

The first systematic review found that buspirone significantly improved symptoms over 4–9 weeks compared with placebo (pooled mean effect size 0.39; absolute numbers and CI not reported; withdrawal rate 17%).The second systematic review found that buspirone significantly improved symptoms compared with placebo (absolute data, confidence intervals, and P values not reported).The third systematic review compared azapirones as a whole versus placebo, but reported data on four RCTs comparing buspirone versus placebo. Three RCTs used the Hamilton Anxiety Scale (HAM-A) as an outcome.One included RCT (21 people) found no significant difference in anxiety between busipirone and placebo (WMD 0.4, 95% CI –5.62 to +6.42); another included RCT (38 people) found that buspirone significantly improved outcome compared with placebo (WMD –7.52, 95% CI –9.89 to –5.15); and the third included RCT (52 people) found that buspirone significantly improved outcome compared with placebo (WMD –3.73, 95% CI –4.01 to –3.45). One included RCT (162 people) reported outcomes based on the Clinical Global Impressions scale (CGI). It found that buspirone significantly improved outcome compared with placebo (CGI much or very improved: RR 1.48, 95% CI 1.01 to 2.17; P = 0.04).

Buspirone versus benzodiazepines:

The first systematic review found one large RCT (240 people), which compared three interventions: buspirone, diazepam, and placebo. It found that a similar proportion of people responded over 6 weeks with buspirone compared with diazepam (response defined as at least 40% reduction in HAM-A score; 54% with buspirone v 61% with diazepam; P values not reported). The third systematic review excluded the large RCT identified by the first review on methods (lack of a formal diagnosis of generalised anxiety disorder [GAD]) and reported data on two other small RCTs.Both RCTs reported data on HAM-A as an outcome. One included three-armed RCT found that lorazepam significantly improved outcome compared with buspirone (40 people; WMD 1.1, 95% CI 0.29 to 1.91) and that alprazolam significantly improved outcome compared with buspirone (39 people; WMD 1.1, 95% CI 0.28 to 1.92). The other included RCT (19 people) found no significant difference between buspirone and diazepam (WMD –0.20, 95% CI –7.45 to +7.05).

Buspirone versus antidepressants:

See benefits of antidepressants.

Buspirone versus hydroxyzine:

See benefits of hydroxyzine.

Harms

Buspirone versus placebo:

The first systematic review gave no information on harms. The second review gave no information about adverse effects of buspirone. One RCT included in the second review found that, compared with placebo, buspirone significantly increased the proportion of people with nausea (240 people; 27/80 [34%] with buspirone v 11/82 [13%] with placebo; RR 2.5, 95% CI 1.3 to 4.7; NNH 5, 95% CI 4 to 14), dizziness (51/80 [64%] with buspirone v 10/82 [12%] with placebo; RR 5.2, 95% CI 2.9 to 9.6; NNH 2, 95% CI 2 to 3), and somnolence (15/80 [19%] with buspirone v 6/82 [7%] with placebo; RR 2.6, 95% CI 1.0 to 6.3; NNH 9, 95% CI 5 to 104).The third review reported that those people on buspirone reported significantly more dizziness and nausea compared with those on placebo (dizziness: 635 people, RR 3.18, 95% CI 1.82 to 5.56; nausea: 429 people, RR 2.16, 95% CI 1.14 to 4.10).

Buspirone versus benzodiazepines:

Diazepam was associated with more fatigue and weakness compared with buspirone, but less headache and dizziness.The third review reported that those people on buspirone reported significantly less drowsiness (RR 0.29, 95% CI 0.21 to 0.41), fatigue (RR 0.24, 95% CI 0.13 to 0.45), nervousness (RR 0.17, 95% CI 0.06 to 0.47), depression (RR 0.22, 95% CI 0.12 to 0.39), insomnia (RR 0.14, 95% CI 0.03 to 0.63), and sleep problems (RR 0.25, 95% CI 0.08 to 0.81) compared with people on benzodiazepines, but significantly more nausea (RR 2.84, 95% CI 1.14 to 7.09) and dizziness (RR 2.28, 95% CI 1.15 to 4.54).

Buspirone versus hydroxyzine:

See harms of hydroxyzine.

Comment

Benzodiazepines versus placebo or buspirone:

A re-analysis of pooled drug company data from eight RCTs comparing benzodiazepines versus placebo or buspirone suggested that recent use of benzodiazepines limited the effectiveness of buspirone in people with generalised anxiety disorder.

Substantive changes

Buspirone in adults One systematic review added;benefits and harms data enhanced, categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Hydroxyzine in adults

Summary

Three RCTs found that, compared with placebo, hydroxyzine improved symptoms of anxiety at 4, 5, or 12 weeks, although in one the RCTs the difference at 5 weeks was not significant. One of the RCTs found that hydroxyzine increased somnolence and headaches compared with placebo. One RCT found no significant difference in the proportion of people who responded after 6 weeks between hydroxyzine and bromazepam. Another RCT found no significant difference in the proportion of people who responded after 4 weeks between hydroxyzine and buspirone.

Benefits

Hydroxyzine versus placebo:

We found one non-systematic review (2 RCTs, 354 people) conducted as part of an RCT protocol, and one additional RCT. The first RCT (110 people) identified by the review found that hydroxyzine 50 mg daily significantly improved Clinical Global Impressions Scale (CGI) scores after 4 weeks compared with placebo (mean improvement: 1.53 with hydroxyzine v 0.95 with placebo; P less than 0.02). The second RCT (244 people entered, 213 people analysed) identified by the review compared three interventions (hydroxyzine, buspirone, and placebo) for 28 days, followed by placebo in all groups for 7 days. It found that hydroxyzine 50 mg daily increased the proportion of people with a Hamilton Anxiety Scale (HAM-A) score reduction of at least 50% at 35 days compared with placebo, although this difference was not significant (30/71 [42%] with hydroxyzine v 20/70 [29%] with placebo; RR 1.50, 95% CI 0.93 to 2.23; analysis not by intention to treat). The additional RCT (369 people) also compared three interventions (hydroxyzine, bromazepam, and placebo) for 12 weeks, followed by placebo in all groups for 1 week. It found that hydroxyzine significantly increased the proportion of people who responded at 42 days compared with placebo (response defined as at least 50% reduction in HAM-A scores from baseline; P = 0.022; absolute numbers presented graphically).

Hydroxyzine versus benzodiazepines:

The additional RCT found no significant difference in the proportion of people who responded at 42 days between hydroxyzine and bromazepam (response defined as a HAM-A score reduction of at least 50%; reported as non-significant, no further data reported).

Hydroxyzine versus buspirone:

The second RCT identified by the non-systematic review also found no significant difference in the proportion of people who responded at 28 days between hydroxyzine and buspirone (response defined as HAM-A score reduction of at least 50%: 30/71 [42%] with hydroxyzine v 26/72 [36%] with buspirone; RR 1.20, 95% CI 0.78 to 1.80).

Harms

Hydroxyzine versus placebo:

The second RCT (244 people) identified by the review found that, compared with placebo, more people taking hydroxyzine had somnolence (AR 10% with hydroxyzine v 0% with placebo) and headaches (AR 6% with hydroxyzine v 1% with placebo). Overall adverse effects were reported in 40% of people taking hydroxyzine and 28% taking placebo.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Abecarnil in adults

Summary

One RCT found limited evidence that low-dose abecarnil improved symptoms compared with placebo. Another RCT found no significant difference in symptoms at 6 weeks between abecarnil and placebo or diazepam. Both RCTs found that, at higher doses, abecarnil increased drowsiness compared with placebo.

Benefits

Abecarnil versus placebo:

We found one systematic review (search date 2002, 4 RCTs) and two multicentre RCTs of abecarnil. The review did not report results for abecarnil versus placebo separately. The first RCT (129 people) compared 3 weeks of treatment with abecarnil in three separate dose regimens (3–9, 7.5–15, and 15–30 mg/day) versus placebo. Within each group the dose was escalated from the minimum to the maximum over the length of the trial. It found that lower doses of abecarnil (3–9 mg/day) significantly improved symptoms compared with placebo (outcome 50% reduction in Hamilton Anxiety Scale score; 19/31 [61%] with abecarnil v 8/26 [31%] with placebo; RR 1.99, 95% CI 1.05 to 3.78). It found no significant difference in symptoms between higher doses of abecarnil and placebo. Results were not calculated by intention to treat (12/34 [35%] people withdrew with abecarnil 15–30 mg/day v 4/35 [11%] with abecarnil 7.5–15 mg/day v 1/32 [3%] with abecarnil 3–9 mg/day v 2/28 [7%] with placebo). The second RCT (310 people) compared three interventions: abecarnil 7.5–17.5 mg daily, diazepam 15–35 mg daily, and placebo. It found no significant difference between abecarnil and placebo in the proportion of people with moderate improvement on the Clinical Global Impressions (CGI) scores at 6 weeks (AR for moderate improvement: 62% with abecarnil v 56% with placebo; reported as non-significant; P values not reported).

Abecarnil versus benzodiazepines:

We found one RCT (310 people) comparing three interventions: abecarnil 7.5–17.5 mg daily, diazepam 15–35 mg daily, and placebo. It found no significant difference between abecarnil and diazepam in the proportion of people with moderate improvement on the CGI scores at 6 weeks (AR for moderate improvement: 62% with abecarnil v 73% with diazepam; reported as non-significant; P values not reported).

Harms

The systematic review gave no information about harms. The first RCT found that abecarnil 3–9 mg daily was associated with fatigue (4/32 [13%] with abecarnil v 0/28 [0%] with placebo), equilibrium loss (2/32 [6%] with abecarnil v 0/28 [0%] with placebo), and drowsiness (10/32 [31%] with abecarnil v 4/28 [14%] with placebo). Higher doses were associated with more adverse effects (62% of people taking abecarnil 15–30 mg experienced at least 1 adverse effect v 51% of people taking abecarnil 7.5–15 mg v 22% with abecarnil 3–9 mg v 21% with placebo). The second RCT gave no information about adverse events.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Antidepressants in adults

Summary

One systematic review found that antidepressants (imipramine, paroxetine, and venlafaxine) improved symptoms over 4–28 weeks compared with placebo. RCTs found that escitalopram improved anxiety outcomes compared with placebo at 8 and 12 weeks. One RCT found that opipramol or paroxetine improved symptoms compared with placebo, and three RCTs found that sertraline improved symptoms compared with placebo. One subsequent RCT found no significant difference in response rates at 24 weeks between venlafaxine and placebo, although a second subsequent RCT found that venlafaxine increased remission. One RCT found limited evidence that escitalopram improved outcomes compared with paroxetine, but other RCTs found no significant difference between different antidepressants. RCTs found no significant difference in effect between antidepressants and benzodiazepines or buspirone. RCTs and observational studies found that antidepressants are associated with sedation, dizziness, nausea, falls, and sexual dysfunction. One RCT found that escitalopram increased rates of sexual dysfunction compared with paroxetine.

Benefits

We found two systematic reviews (search date 2002, 8 RCTs, 2058 people; and search date 2002, 7 RCTs), four additional RCTs, and eight subsequent RCTs (see table 2 ).

Table 2.

Studies examining effects of antidepressants(see text).

Study design, ref	Population	Comparison	Outcome	Timeline	Results
Any antidepressant v placebo

Systematic review	4 RCTs, 1056 people	Antidepressants (imipramine, paroxetine, and venlafaxine) v placebo	Non-response rate	8–28 weeks	277/606 (46%) with antidepressants v 280/449 (62%) with placebo; RR of not responding 0.70, 95% CI 0.62 to 0.79; NNT 6, 95% CI 5 to 9

Systematic review	1 RCT, 230 people	Imipramine v trazodone v diazepam v placebo	Proportion of people with participant-assessed global improvement	8 weeks	73% with imipramine v 67% with trazodone v 66% with diazepam v 39% with placebo; results not analysed by intention to treat; P less than 0.026 for comparisons versus placebo

Escitalopram v placebo

RCT	315 people	Escitalopram 10–20 mg/day v placebo	Remission (defined as a score of 7 or less on HAMA-A)	8 weeks	36% with escitalopram v 16% with placebo; P less than 0.01; mean difference: 3.9, 95% CI 1.7 to 6.0
			Response rate (CGI score of 1 or 2)	8 weeks	58% with escitalopram v 38% with placebo; P = 0.01
RCT	681 people	Escitalopram at 5 mg/day, 10 mg/day, and 20 mg/day v placebo	Mean difference in HAM-A over 12 weeks	12 weeks	There was a significant difference between escitalopram 10 mg daily and 20 mg daily and placebo, no significant difference between escitalopram 5 mg daily and placebo (mean change: placebo –14.2, 5 mg escitalopram –15.49 [v placebo P = 0.165], 10 mg escitalopram –16.8 [v placebo P = 0.006], 20 mg escitalopram –16.4 [v placebo P = 0.022],

Pooled analysis of 3 RCTs	3 RCTs, 856 people	Escitalopram v placebo	Mean improvement in HAM-A psychic anxiety subscale from baseline	8 weeks	5.8 with escitalopram v 3.9 with placebo; P less than 0.001
			Mean improvement in HAM-A somatic anxiety subscale from baseline	8 weeks	4.3 with escitalopram v 3.7 with placebo; P = 0.02
			Rates of HAM-A response (defined as at least 50% improvement in mean HAM-A score)	8 weeks	48% with escitalopram v 29% with placebo; P less than 0.001
			Rates of CGI-I response (defined as CGI-I score of 1 or 2 [much or very much improved] plus remission [HAM-A 7 or less])	8 weeks	52% with escitalopram v 37% with placebo; P less than 0.001
Imipramine v placebo

Systematic review	1 RCT, 113 people	Imipramine v placebo	Response rate	8–28 weeks	RR 0.67, 95% CI 0.50 to 0.91; NNT 4, 95% CI 3 to 14

Opipramol v placebo

RCT	318 people	Opipramol (a TCA with minimal serotonin reuptake blocking properties) v alprazolam v placebo Duration: 28 days	Response (defined as CGI scale score of less than 2) rate	28 days	63/100 (63%) with opipramol v 50/107 (47%) with placebo; RR 1.35, 95% CI 1.05 to 1.69; NNT 7, 95% CI 1 to 26

Paroxetine v placebo

Systematic review	1 RCT, 324 people	Paroxetine v placebo	Non-treatment response (measured using CGI scores, HAM-A scores and Sheehan disability scale scores)	8 weeks	RR 0.72, 95% CI 0.56 to 0.92; NNT 6.72, 95% CI 3.9 to 24.7

RCT	565 people	Paroxetine 20 mg/day v placebo	Response (defined as CGI scores 2 or less)	8 weeks	116/188 (62%) v 82/180 (45%); RR 1.36, 95% CI 1.11 to 1.64; NNT 6, 95% CI 4 to 13
		Paroxetine 40 mg/day v placebo	Response (defined as CGI scores 2 or less)	8 weeks	134/197 (68%) v 82/180 (45%); RR 1.49, 95% CI 1.24 to 1.79; NNT 4, 95% CI 3 to 6
Sertraline v placebo

RCT	373 people	Sertraline (dose titrated from 25 mg/day in the first week to 50–150 mg/day by week 12) v placebo	HAM-A score (mean change from baseline)	12 weeks	−11.7 with sertraline v −8.0 with placebo; P less than 0.0001
			Anxiety component of HAD scale (mean change from baseline)	12 weeks	−4.5 with sertraline v −2.6 with placebo; P less than 0.0001
			CGI (mean change from baseline at end point)	12 weeks	−1.56 with sertraline v −0.90 with placebo; P less than 0.0001
			Quality of Life Enjoyment and Satisfaction Questionnaire (mean change from baseline)	12 weeks	9.0% with sertraline v 2.4% with placebo; P less than 0.0001
RCT	373 people	Sertraline v placebo	HAM-A score improvement	12 weeks	Mean ratio: 1.5, 95% CI 1.3 to 1.6; mean difference: 3.7, 95% CI 3.5 to 3.9
			CGI score improvement	12 weeks	Mean ratio: 1.33, 95% CI 1.27 to 1.3; mean difference: 0.40, 95% CI 0.34 to 0.46
			Response rates (30% reduction in HAM-A)	12 weeks	73% with sertraline v 40% with placebo; P = 0.001; absolute data not reported
			Response rates (50% reduction in HAM-A)	12 weeks	55% with sertraline v 32% with placebo; P = 0.001; absolute data not reported
RCT	326 people	Sertraline 50–200 mg/day v placebo	Reduction in HAM-A total score from baseline	10 weeks	–12.71 with sertraline v –11.5 with placebo; P = 0.032
Venlafaxine v placebo

Systematic review	1 RCT, 365 people	Venlafaxine 75 or 150 mg/day v buspirone 30 mg/day v placebo	Response rates (response defined as CGI score of 1 or 2)	8 weeks	54/87 (62%) with venlafaxine 75 mg; P = 0.002 v 44/89 (49%) with venlafaxine 150 mg; P value not reported v 52/95 (55%) with buspirone; P = 0.03 v 38/98 (39%) with placebo; P values for comparisons v placebo.
Systematic review	2 RCTs, 558 people	Venlafaxine v placebo	Non-treatment response	8–28 weeks	RR 0.68, 95% CI 0.46 to 0.99; NNT 5.0, 95% CI 3.58 to 8.62

RCT	244 people with GAD and depression, recruited from general practice	Venlafaxine (sustained release 75–150 mg/day) v placebo	Response (defined as a 50% reduction in HAM-A)	24 weeks	52% with venlafaxine v 48% with placebo; P = 0.68
			Remission (defined as HAM-A score of greater than 7)	24 weeks	27.9% with venlafaxine v 18.9% with placebo; P = 0.11
			CGI score 1 or 2 (meaning "much" or "very much" improved)	24 weeks	65% with venlafaxine v 46% with placebo; P = 0.003

RCT	42 people	Venlafaxine 75 mg/day v placebo	Remission rate (defined as a score of 7 or less on HAM-A)	8 weeks	15/24 (63%) with venlafaxine v 2/22 (9%) with placebo; P = 0.0006
			HAM-A (mean change from baseline)	8 weeks	−19.2 with venlafaxine v −10.8 with placebo; P less than 0.001
			CGI-Severity (mean change from baseline)	8 weeks	−2.4 with venlafaxine v −1.2 with placebo; P = 0.002
			CGI-Improvement (mean change from baseline)	8 weeks	−1.8 with venlafaxine v −0.6 with placebo; P = 0.012
			Covi Anxiety Scale (mean change from baseline)	8 weeks	−4.8 with venlafaxine v −3.3 with placebo; P = 0.056

RCT	544 people	Venlafaxine 37.5 mg/day v placebo	People with moderately impaired social function	6 months	78/125 (62%) with venlafaxine 37.5 mg/day v 63/111 (56%) with placebo; significance not reported
		Venlafaxine 75 mg/day v placebo		6 months	83/115 (72%) with venlafaxine 75 mg/day v 63/111 (56%) with placebo; significance not reported
		Venlafaxine 150 mg/day v placebo		6 months	94/118 (80%) with venlafaxine 150 mg/day v 63/111 (56%) with placebo; significance not reported

Antidepressants v each other

RCT	121 people	Escitalopram versus paroxetine	Response (defined as CGI-I of 1 or 2)	24 weeks	RR 1.25, 95% CI 0.99 to 1.59
			HAM-A scale		Mean difference: 2.0, 95% CI 0.63 to 4.63
			CGI-I scale		Mean difference: 0.3, 95% CI –0.77 to +1.37

Systematic review	1 RCT, 81 people	Paroxetine v imipramine	Proportion of people who failed to respond	8 weeks	3/36 (8%) with paroxetine v 2/30 (7%) with imipramine; RR of failing to respond 1.73, 95% CI 0.31 to 9.57
RCT	55 people	Paroxetine v sertraline	Rate of response (defined as 50% reduction in HAM-A)	8 weeks	17/25 (68%) with paroxetine v 17/28 (61%) with sertraline; reported as not significant; RR 1.1, 95% CI 0.7 to 1.6
			Rate of remission (defined HAM-A less than 7)		10/25 (40%) with paroxetine v 14/28 (50%) with sertraline; RR 0.8, 95% CI 0.4 to 1.4
			CGI rating “normal”		10/25 (40%) with paroxetine v 13/28 (46%) with sertraline; reported as not significant; RR 0.8, 95% CI 0.5 to 1.5
RCT ]	1 multi-arm RCT, 270 in these two arms	Escitalopram 10 mg daily v paroxetine 20 mg daily.	Mean change in HAM-A	12 weeks	HAM-A mean difference –2.06, 95% CI –3.90 to–-0.21
Antidepressants v benzodiazepines

Systematic review	1 RCT, 81 people	Imipramine v 2'-chlordesmethyldiazepam	Anxiety (mean HAMA-A score)	8 weeks	10.8 with imipramine v 12.9 with 2'-chlordesmethyldiazepam; P = 0.05
RCT	318 people	Opipramol v alprazolam	Response (defined as CGI scale score of less than 2)	28 days	63% with opipramol v 64% with alprazolam; significance assessment not reported
Systematic review	1 RCT, 81 people	Paroxetine v 2'-chlordesmethyldiazepam	Anxiety (mean HAMA-A score)	8 weeks	11.1 with paroxetine v 12.9 with 2'-chlordesmethyldiazepam; P = 0.05
RCT	80 people	Paroxetine v lorazepam	HAM-A improvement	6 weeks	13.7 with paroxetine v 10.8 with loraxepam; P greater than 0.05
			SAS		16.5 with paroxetine v 14.4 with loraxepam; P greater than 0.05
			Recovery		18/40 with paroxetine v 16/40 with loraxepam; P greater than 0.05
Antidepressants v buspirone

Systematic review	1 RCT, 365 people	Venlafaxine 75 mg/day v buspirone 30 mg/day	Rates of response (defined as CGI score of 1 or 2)	8 weeks	54/87 (62%) with venlafaxine 75 mg v 52/95 (55%) with buspirone; P values not reported
		Venlafaxine 150 mg/day v buspirone 30 mg/day	Rates of response (defined as CGI score of 1 or 2)	8 weeks	44/89 (49%) with venlafaxine 150 mg v 52/95 (55%) with buspirone; P values not reported

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CGI, Clinical Global Impression Scale; HAD, Hospital Anxiety and Depression scale; HAM-A, Hamilton Anxiety Rating Scale; Ref, reference; SAS, Self-rating Anxiety Scale.

Any antidepressant versus placebo:

One systematic review found that antidepressants (imipramine, paroxetine, and venlafaxine) significantly increased the proportion of people who responded at 8–28 weeks compared with placebo (see table 2 ).

Escitalopram versus placebo:

One additional RCT (315 people) found that escitalopram significantly increased rates of remission and response compared with placebo at 8 weeks (see table 2 ). We found one report of pooled data from three RCTs (total of 856 people) comparing escitalopram versus placebo. It found that escitalopram significantly increased rates of response and Hamilton Anxiety Scale (HAM-A) psychic and somatic anxiety subscales at 8 weeks compared with placebo (see table 2 ). A re-analysis of the same trials found a pooled effect size of 0.3 compared with placebo.One subsequent RCT (681 people) compared three different doses of escitalopram (5, 10, and 20 mg daily), paroxetine, and placebo.The RCT found that escitalopram at the two higher doses (10 and 20 mg/day) significantly improved mean HAM-A scores at 12 weeks compared with placebo, and found no significant difference between escitalopram at the lower dose (5 mg/day) and placebo (see table 2 ). It found that remission (defined as a HAM-A score less than 7) was significantly more likely to occur with all three doses of escitalopram than with placebo (all P less than 0.05).Another subsequent RCT compared continued escitalopram 20 mg daily over 24 to 76 weeks versus placebo in 375 people, and reported time to relapse. Initially, 491 people had been treated with 12 weeks of open-label escitalopram. The RCT population was 375 (77%) people who had responded to escitalopram and had a HAM-A score of 10 or less. These people were then randomised to escitalopram or placebo. Time to relapse was defined as a HAM-A score of 15 or above. At 24 weeks, the RCT found that escitalopram significantly reduced the proportion of people who had relapsed compared with placebo (34/187 [18%] with escitalopram v 98/188 [52%] with placebo, P less than 0.001).It also found that escitalopram significantly increased the time to relapse compared with placebo (Kaplan–Meier analysis, presented graphically, P less than 0.001).

Opipramol versus placebo:

One RCT identified by the second review found that opipramol significantly increased response rate after 28 days compared with placebo (see table 2 ).

Paroxetine versus placebo:

The first review included one RCT (324 people), which found that paroxetine improved rates of treatment response compared with placebo at 8 weeks (see table 2 ). The first additional RCT found that paroxetine (20 or 40 mg/day) significantly increased response rates compared with placebo (see table 2 ).One subsequent multi-arm RCT found no significant difference between paroxetine (20 mg/day) and placebo in symptoms measured by HAM-A scores over 12 weeks (274 people in analysis; mean change in HAM-A total score: difference between groups –0.51, 95% CI –2.33 to +1.32; P = 0.585). However, it found that paroxetine was significantly better in improving outcomes measured by mean Clinical Global Impression-Improvement (CGI-I) scores compared with placebo at weeks 4, 8, and 10 (results presented graphically, P less than 0.05).

Sertraline versus placebo:

One additional RCT (373 people) found that sertraline significantly improved scores for the HAM-A, the anxiety component of Hospital Anxiety and Depression Scale, Clinical Global Impressions Scale (CGI), and Quality of Life Enjoyment and Satisfaction Questionnaire at 12 weeks (see table 2 ). One subsequent RCT (randomisation method not described; 373 people) found that sertraline significantly improved HAM-A and CGI scores at 12 weeks compared with placebo (see table 2 ).Another subsequent RCT (338 people) compared sertraline at a flexible dose versus placebo over 10 weeks. The RCT found that sertaline significantly improved scores for HAM-A compared with placebo (see table 2 ). It found that the response rate (defined as at least a 50% decrease in HAM-A score) was 59.2% with sertraline compared with 48.2% for placebo (P = 0.050): if response was defined as a CGI-I score of 1 or 2, it was 64.6% with sertraline compared with 54.3% with placebo (P = 0.057).

Venlafaxine versus placebo:

The first systematic review found that venlafaxine significantly increased the proportion of people who responded at 8–28 weeks compared with placebo. It also found that venlafaxine significantly increased response rates compared with placebo. A later report of one RCT (544 people) included in the first review found that venlafaxine reduced the proportion of people with moderately impaired social function at 6 months compared with placebo, and suggested a dose–response relationship (see table 2 ). The second systematic review concluded that venlafaxine improved symptoms compared with placebo (5 RCTs or CCTs, 1626 people, absolute data, confidence intervals, and P values not reported). However, one of the RCTs (244 people) included in the second review found no significant difference between venlafaxine and placebo in response or remission at 24 weeks (see table 2 ). One additional RCT (42 people) found that venlafaxine significantly improved remission rate and HAM-A scores at 8 weeks compared with placebo. It found significant but small improvements with venlafaxine in CGI outcomes compared with placebo. It found no significant difference in Covi anxiety scale (see table 2 ).

Antidepressants versus each other:

The first systematic review identified one RCT (56 people), which found no significant difference in the proportion of people who responded over 8 weeks of treatment between paroxetine and imipramine (see table 2 ). One subsequent RCT (55 people) comparing paroxetine versus sertraline found no significant difference in rates of response or “normal” CGI Scale (see table 2 ). Another subsequent RCT (method of randomisation not reported; 121 people) comparing escitalopram versus paroxetine found limited evidence of significantly improved HAM-A scores with paroxetine compared with escitalopram. It found limited evidence of no significant difference between groups in response rates (CGI-I of 1 or 2) or CGI-I (see table 2 ). However, these results should be interpreted with caution, as there were differences in withdrawal rates between groups, and discontinuation syndrome (see harms below). Another subsequent RCT which compared three different fixed doses of escitalopram (5, 10, and 20 mg/day) versus placebo also contained a paroxetine arm. The RCT found that escitalopram 10 mg daily significantly improved HAM-A scores compared with paroxetine 20 mg daily (intention-to-treat analysis using last observation carried forward, HAM-A mean difference: –2.06, 95% CI –3.90 to –0.21) (see table 2 ). It did not report an intention-to-treat analysis for the other two dosages of escitalopram versus paroxetine. It found a significant difference in response (defined as at least a 50% decrease in HAM-A) in favour of escitalopram 10 mg compared with paroxetine (ITT using last observation carried forward: 72% with escitalopram 10 mg v 60% with paroxetine; P less than 0.05), and it also found a significant difference in remission (defined as HAM-A less than 7) at the same dose (48% with escitalopram 10 mg v 33% with paroxetine, P less than 0.05).

Antidepressants versus benzodiazepines:

The first review included two RCTs, and the second review included one RCT, and we found one subsequent RCT (see table 2 ). The first RCT identified by the first review found similar improvements with imipramine, trazodone, diazepam, and placebo, but did not directly compare the significance of differences between groups. The second RCT identified by the first review found that paroxetine significantly improved anxiety after 8 weeks compared with 2'-chlordesmethyldiazepam. The RCT included in the second review found no significant difference in response rates at 28 days between opipramol and alprazolam at (see table 2 ). The subsequent RCT found no significant difference in HAM-A or Self-rating Anxiety Scale (SAS) scores, or in rates of recovery, between paroxetine and lorazepam (see table 2 ).

Antidepressants versus buspirone:

One RCT identified by the first review found similar response rates at 8 weeks between venlafaxine and buspirone (see table 2 ).

Harms

Antidepressants versus placebo:

The first review found that people taking venlafaxine were more likely to report nausea, dry mouth, insomnia, constipation, flatulence, anorexia, somnolence, and sexual dysfunction than people taking placebo. One included RCT reported sedation, confusion, dry mouth, and constipation with both imipramine and trazodone. One subsequent RCT reported asthenia, constipation, dry mouth, abnormal ejaculation, decreased libido, nausea, somnolence, decreased appetite, sweating, yawning, and female genital disorders. The adverse events were significantly more frequent with paroxetine compared with placebo (at least 1 adverse event: 88% with paroxetine 20 mg/day v 86% with paroxetine 40 mg/day v 74% with placebo; P less than 0.002). One subsequent RCT reported headache, nausea, somnolence, and upper respiratory tract infection with both escitalopram and placebo (headache: 23.4% with escitalopram v 17.8% with placebo; nausea: 19.0% with escitalopram v 8.9% with placebo; somnolence: 12.0% with escitalopram v 5.7% with placebo; upper respiratory tract infection: 11.4% with escitalopram v 7.6% with placebo; significance not reported). One subsequent RCT reported nausea, sweating, constipation, and dry mouth (adverse events: 41.7% with venlafaxine v 40.9% with placebo; significance not reported). One RCT included in the second review reported nausea, somnolence, dry mouth, sweating, constipation, anorexia, and sexual dysfunction with venlafaxine (nausea: 31% with venlafaxine v 10% with placebo; sweating: 13.1% with venlafaxine v 1.7% with placebo; P value not reported). Most of the adverse effects (apart from dizziness and sexual dysfunction) decreased over 6 months in those who continued taking the medication. There have been case reports of nausea in people taking paroxetine. One RCT (121 men and women) reported increased overall adverse events with paroxetine compared with escitalopram (89% with paroxetine v 77% with escitalopram), but found that escitalopram significantly increased rates of sexual dysfunction compared with paroxetine (ejaculation disorder: 30% with escitalopram v 14% with paroxetine; decreased libido: 26% v 5%; anorgasmia: 26% v 7%; P values not reported, reported as significant; some analyses one sex only).Another subsequent RCT found that 6.5% (9/139) of people treated with paroxetine 20 mg daily over 12 weeks complained of anorgasmia compared with 4.4% (6/136) of people receiving escitalopram 10 mg daily and 0% (0/139) in the placebo arm (reported as P less than 0.05).In this five-arm RCT, which compared escitalopram (at 3 fixed doses), paroxetine, and placebo, around 10% of people in all medication arms complained of insomnia, compared with 2% taking placebo. The RCT also found that escitalopram 10 mg daily (10.3% of people) and 20 mg daily (16.5% of people) led to significantly more complaints of fatigue than placebo (2.9%; P less than 0.05). It found that escitalopram 5 mg daily (9.7% of people), 10 mg daily (9.6%), and 20 mg daily (9.8%) were associated with significantly more complaints of diarrhoea than placebo (2.9%; P less than 0.05). In another RCT over 10 weeks, sertraline was associated with a significant increase in diastolic blood pressure compared with placebo (mean change: +1.59 mm Hg with sertraline v -0.63 mm Hg with placebo, P = 0.02) and was also associated with a significantly greater mean weight loss compared with placebo (mean loss: –1.94 lb with sertraline v +1.07 lb with placebo, P = 0.0002).

Adverse effects when discontinuing treatment:

Abrupt discontinuation of SSRIs has been associated with adverse effects including dizziness, headache, nausea, vomiting, diarrhoea, movement disorders, insomnia, irritability, visual disturbance, lethargy, anorexia, and lowered mood. One RCT (120 people receiving maintenance SSRIs for depression) found that significantly more people had adverse effects when discontinuing paroxetine or sertraline compared with people discontinuing fluoxetine (60% with paroxetine v 66% with sertraline v 16% with fluoxetine; P less than 0.01 for paroxetine or sertraline v fluoxetine).In a 12-week trial of escitalopram, paroxetine, and placebo, there was a significant increase in scores with paroxetine on the Discontinuation Emergent Signs and Symptoms (DESS) scale at day 7 compared with placebo (4.2 with paroxetine v 0.4 with placebo, P less than 0.001).

Overdose:

In a series of 239 coroner-directed necropsies from 1970–1989, TCAs were considered a causal factor in 12% of deaths, and hypnosedatives (primarily benzodiazepines and excluding barbiturates) in 8%.

Accidental poisoning:

TCAs are a major cause of accidental poisoning. A study estimated that there was one death for every 44 children admitted to hospital after ingestion of TCAs.

Hyponatraemia:

One case series reported 736 incidents of hyponatraemia in people taking SSRIs; 83% of episodes were in hospital inpatients aged over 65 years. It is not possible to establish causation from this type of data.

Falls:

One retrospective cohort study (2428 elderly residents of nursing homes) found an increased risk of falls in new users of antidepressants (665 people taking TCAs; adjusted RR 2.0, 95% CI 1.8 to 2.2; 612 people taking SSRIs; adjusted RR 1.8, 95% CI 1.6 to 2.0; and 304 people taking trazodone; adjusted RR 1.2, 95% CI 1.0 to 1.4). The increased rate of falls persisted through the first 180 days of treatment and beyond. One case control study (8239 people aged at least 66 years, treated in hospital for hip fracture) found an increased risk of hip fracture in those taking antidepressants (SSRIs: adjusted OR 2.4, 95% CI 2.0 to 2.7; secondary amine TCAs such as nortriptyline: adjusted OR 2.2, 95% CI 1.8 to 2.8; and tertiary amine TCAs such as amitriptyline: adjusted OR 1.5, 95% CI 1.3 to 1.7). This study could not control for confounding factors; people taking antidepressants may be at increased risk of hip fracture for other reasons.

In pregnancy:

We found no reports of harmful effects in pregnancy. One case control study found no evidence that imipramine or fluoxetine increased the rate of malformations in pregnancy. The US Food and Drug Administration issued a public health advisory in response to new research about a potential risk of congenital malformations after maternal use of paroxetine (Seroxat) during the first trimester. However, other epidemiological studies did not support such an increased risk, and data are being actively investigated by the Commission on Human Medicines (CHM) and Medicines and Healthcare products Regulatory Agency (MHRA).

Sexual dysfunction:

A survey (1022 people mostly suffering from depression; 610 women) of people using antidepressants with acceptable sexual function before antidepressant treatment reported the incidence of sexual dysfunction (decreased desire, delayed ejaculation, and anorgasmia) to be 71% with paroxetine, 67% with venlafaxine, and 63% with fluvoxamine.One RCT found that, over 10 weeks, sertraline was associated with a significant decrease in libido compared with placebo (29/165 [18%] with sertraline v 4/163 [2%] with placebo, P less than 0.01). Among men, 12/67 (17.9%) had sexual dysfunction, most commonly abnormal orgasm (7/67 [10.4%]) and ejaculation failure (4/67 [6%]). No one in the placebo arm reported abnormal orgasm or ejaculation failure.

Suicide:

See harms of prescription antidepressant drugs for mild, moderate, or severe depression in review on depression in adults (drug and other physical treatments).

Comment

The more recent RCTs comparing one antidepressant with another are better powered to detect any difference between antidepressants.

Substantive changes

Antidepressants in adults Three RCTs added; benefits and harms data enhanced, categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Antipsychotics in adults

Summary

One large RCT identified by a systematic review found that trifluoperazine improved symptoms compared with placebo. One small RCT in people with treatment-resistant generalised anxiety disorder (GAD), identified by two systematic reviews, found insufficient evidence on the effects of olanzapine versus placebo. Antipsychotics are associated with a range of well-documented adverse effects, some of which are serious and irreversible, and therefore they should be used with caution.

Benefits

We found one systematic review on the use of antipsychotics for primary and comorbid anxiety disorders,and one systematic review on the use of antipsychotics as augmentation in treatment-resistant anxiety disorders. The first systematic review (search date 2005) included three RCTs of older antipsychotics. It did not pool data. One included RCT (413 people) found that trifluoperazine 2–6 mg daily significantly improved outcomes measured by Hamilton Anxiety Scale (HAM-A) score compared with placebo (absolute numbers not reported; P less than 0.001). A second included RCT (31 people) found no significant difference in outcomes between flupenthixol and placebo (absolute numbers not reported; reported as not significant, P value not reported). The third included RCT (139 people) found similar effects in median change in HAM-A scores between chlorprothixene and placebo (median reductions in HAM-A scores: 10.3 with chlorprothixene v 7.3 with placebo, statistical analysis between groups not reported). However, the RCT was short (2 weeks) which may not have allowed any differences in outcomes between treatments to become apparent. The first systematic review also included one RCT of olanzapine in treatment-resistant GAD which was included in the second systematic review and is reported below. The second systematic review (search date 2005) included RCTs in people with treatment-refractory anxiety disorders treated with antipsychotics.Of the included RCTs, two were in people with GAD. The first included RCT (21 people who had not responded to fluoxetine) found that olanzapine significantly reduced symptoms measured by HAM-A compared with placebo (SMD –0.98, 95% CI –1.9 to –0.05). However, only nine people recieved olanzapine in the olanzapine treatment group, which is below BMJ Clinical Evidence criteria of having at least 10 people per treatment group. The review reported that "this finding was replicated" in the other 5-week RCT (39 people) of risperidone compared with placebo (further numerical data not reported, P value not reported). This RCT was not further analysed by the review as it failed to provide sufficient information on a standardised scale to determine whether the included population was treatment resistant.

Harms

The RCT included in the first reviewreported more cases of drowsiness (43% with trifluoperazine v 25% with placebo) and extrapyramidal reactions and movement disorders (17% with trifluoperazine v 8% with placebo) with trifluoperazine than with placebo.The second review did not separately report harms for the two included RCTs in people with GAD.The review included RCTs of antipsychotics in a range of treatment-resistant disorders. It reported that, in general, the most common adverse effect with antipsychotics across the range of included RCTs was sedation/somnolence, which was experienced by 20% of people in the 11 RCTs which reported data on medication tolerance. It also reported that, in general in these RCTs, other adverse effects commonly reported with antipsychotic augmentation included weight gain, nausea, dizziness, dry mouth, gastrointestinal distress, and increased appetite. See review on schizophrenia.

Comment

Clinical guide:

Any benefits of antipsychotic treatment must be weighed against the risks of movement disorders, parkinsonian adverse effects (including depressed mood and poor concentration), and endocrine dysfunction associated with weight gain. We note that the most recent systematic review is (appropriately) only reviewing trials in people where other approaches have failed.

Substantive changes

Antipsychotics in adults Two systematic reviews added; benefits and harms data enhanced, categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Pregabalin in adults

Summary

Two RCTs found that pregabalin improved Hamilton Anxiety Scale scores at 4 weeks compared with placebo. One RCT found no significant difference in Hamilton Anxiety Scale scores at 4 weeks between pregabalin and lorazepam, whereas another RCT found that, at 4 weeks, pregabalin improved anxiety compared with alprazolam. Adverse effects associated with pregabalin included somnolence, dizziness, and headache.

Benefits

Pregabalin versus placebo:

We found two RCTs. The first RCT (271 people) was a four-arm trial comparing pregabalin 50 and 200 mg daily, lorazepam 2 mg daily, and placebo. It found that pregabalin 200 mg daily significantly improved Hamilton Anxiety Scale (HAM-A) total scores at 4 weeks compared with placebo (mean difference: –3.90, 95% CI –6.26 to –1.54; P = 0.0013) but found no significant difference between pregabalin 50 mg daily and placebo (mean difference: –1.62, 95% CI –3.90 to +0.67; P greater than 0.16). It found higher rates of response (defined as at least 50% improvement in HAM-A score or Clinical Global Impressions Scale (CGI) rating of “very much improved” or “much improved”) with pregabalin compared with placebo, although these differences were not significant (HAM-A: 29/66 [44%] with placebo v 36/69 [52%] with pregabalin 50 mg/day [P greater than 0.34] v 36/62 [59%] with pregabalin 200 mg/day [P greater than 0.09]; all P values for comparison against placebo). The second RCT (454 people, randomised in blocks of 10) compared pregabalin (300 mg/day, 450 mg/day, or 600 mg/day) versus alprazolam (1.5 mg/day) versus placebo. It found that all doses of pregabalin were more effective than placebo at improving HAM-A scores from baseline at 4 weeks, although this difference was not significant for pregabalin 450 mg daily (mean difference from placebo in reduction in HAM-A score: pregabalin 300 mg/day: −3.89, 95% CI −6.05 to −1.73; P less than 0.001; pregabalin 450 mg/day: −2.65, 95% CI −4.82 to −0.48; P = 0.2; pregabalin 600 mg/day: −3.43, 95% CI −5.62 to −1.25; P = 0.02).

Pregabalin versus benzodiazepines:

We found two RCTs. The first RCT (271 people) was a four-arm trial comparing pregabalin 50 and 200 mg daily, lorazepam 2 mg daily, and placebo. Secondary analysis found no significant difference in improvements in HAM-A total scores at 4 weeks between lorazepam 2 mg daily and pregabalin 200 mg daily (P greater than 0.1) or pregabalin 50 mg daily (P greater than 0.5). The second RCT (454 people randomised in blocks of 10) compared pregabalin (300 mg/day, 450 mg/day, or 600 mg/day) versus alprazolam (1.5 mg/day) and placebo. It found that pregabalin increased HAM-A and CGI-Improvement (CGI-I) scores compared with alprazolam 1.5 mg daily. It found significantly higher response rates (defined as at least 50% improvement in HAM-A score or CGI rating of “very much improved” or “much improved”) at 4 weeks with pregabalin 300 mg daily than with alprazolam (CGI-I: 61% v 45%; P less than 0.05; HAM-A: 61% v 43%; P less than 0.05; absolute data not reported, results presented graphically).

Harms

Pregabalin versus placebo:

The first RCT found an increased proportion of people with adverse events in the treatment groups compared with placebo (59 [89%] with pregabalin 200 mg/day v 51 [73%] with pregabalin 50 mg/day v 45 [67%] with placebo; significance not reported). Most adverse effects were mild or moderate — most commonly somnolence, dizziness, headache, and dry mouth.

Pregabalin versus benzodiazepines:

The first RCT found a similar frequency of overall adverse events between the highest dose of pregabalin and lorazepam (62/68 [91%] with lorazepam v 59/66 [89%] with pregabalin 200 mg/day v 51/70 [73%] with pregabalin 50 mg/day). Most adverse effects were mild or moderate — most commonly somnolence, dizziness, headache, and dry mouth. Somnolence was most common with lorazepam, dizziness with pregabalin 200 mg daily, and headache and dry mouth with any dose of pregabalin than with lorazepam.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 20;2007:1002.

CBT in children and adolescents

Summary

RCTs identified by systematic reviews and subsequent RCTs in children and adolescents with generalised anxiety disorder (but also other anxiety disorders as well) found CBT-related improvements in remission rates and/or reduced symptoms compared with waiting list controls. We found no RCTs in children or adolescents with generalised anxiety disorder alone, or in children below the age of six years.

Summary

One small RCT in children and adolescents with generalised anxiety disorder (GAD) found that sertraline improved symptoms compared with placebo. One RCT in children and adolescents with GAD (but also other anxiety disorders as well) found that fluoxetine improved symptoms compared with placebo. Another RCT in children and adolescents with GAD (but also other anxiety disorders as well) found that fluvoxamine improved symptoms compared with placebo. The RCTs found that fluoxetine and fluvoxamine increased abdominal discomfort compared with placebo. The use of antidepressants in general in children and adolescents has been the subject of adverse events warnings regarding self-harm and other potential serious adverse effects.

Benefits

Sertraline versus placebo:

The small RCT included in the systematic reviewcompared sertraline versus placebo in 22 children and adolescents aged 5–17 years with childhood GAD. Children and adolescents were assigned to sertraline (50 mg/day maximum) or placebo. It found that, from week 4 of treatment, sertraline significantly improved symptoms as measured by the Hamilton Anxiety Scale (HAM-A) and the Clinical Global Impressions Scale (CGI) compared with placebo (week 9: mean HAM-A total score; 7.8 with setraline v 21 with placebo, P less than 0.001; mean CGI score; 2.4 with sertraline v 3.9 with placebo, P less than 0.001).

Fluoxetine versus placebo:

One subsequent RCT (74 children and adolescents aged 7–17 years) compared fluoxetine (20 mg daily) versus placebo in participants with GAD, separation anxiety disorder, and/or social phobia (47/74 [64%] had GAD either with or without another disorder).The RCT found that fluoxetine reduced anxiety symptoms and improved functioning across all measures. It found that fluoxetine significantly increased the proportion of people who were much or very much improved compared with placebo (defined as Clinical Global Impression-Improvement (CGI-I) score 2 or less; intention-to-treat analysis, 61% [22/36] with fluoxetine v 35% [ 13/37] with placebo, P = 0.03). In subgroup analysis, it found that people with GAD randomised to fluoxetine had a significantly better clinical response compared with placebo (CGI-I score 2 or less; 46 people, 67% with fluoxetine v 36% with placebo, P = 0.04).

Fluvoxamine versus placebo:

One subsequent RCT (128 people) compared fluvoxamine (300 mg/day, maximum) versus placebo in young people with anxiety disorders including GAD, social phobia, or separation anxiety disorder (57% [73/128] had GAD with or without another disorder).Study participants were aged 6 to 17 years, and had previously received 3 weeks of psychological treatment without benefit. The RCT found that fluvoxamine significantly improved anxiety and response to treatment compared with placebo (Pediatric Anxiety Rating Scale, mean decrease: 9.7 with fluvoxamine v 3.1 with placebo, P less than 0.001; CGI-I scale, response defined as score less than 4: 76% [48/63] with fluvoxamine v 29% [19/65] with placebo, P less than 0.001).

Harms

Sertraline versus placebo:

The small RCT found no statistically significant differences in adverse events between the sertraline and placebo groups. There was a non-significant trend for children receiving sertraline to report less dizziness, nausea, and stomach pain than the placebo group. Participants receiving sertraline reported numerically (but not significantly) more incidences of dry mouth, drowsiness, leg spasms, and restlessness.

Fluoxetine versus placebo:

The RCT found that significantly more children with fluoxetine had gastrointestinal adverse effects (abdominal pain and nausea) during the first two weeks of treatment compared with placebo (16/35 [46%] with fluoxetine v 7/32 [22%] with placebo, P = 0.04). Five children receiving fluoxetine were removed from the study due to (non-significant) incidences of excitement, giddiness, or disinhibition. An association between fluoxetine and mild, transient headaches was also noted during the first two weeks of treatment (neurological complaints [drowsiness and headaches]: 16/36 [44%] with fluoxetine v 5/36 [14%] with placebo, P = 0.004).

Fluvoxamine versus placebo:

The RCT found that abdominal discomfort was significantly more frequent in the fluvoxamine group than in the placebo group (49% with fluvoxamine v 28% with placebo, P = 0.02).A trend was also noted towards a higher frequency of increased motor activity in the fluvoxamine group, but the difference between groups was not significant (27% with fluvoxamine v 8% with placebo, P = 0.06).

General harms:

See review on depression in adults (drug and other physical treatments). One review of suicidality and antidepressant use in pediatric patients (most of whom were diagnosed with major depression) found a modest increase in suicide risk associated with antidepressants. However, a recent meta-analysis of RCTs of second-generation antidepressants in the treatment of pediatric depressive and anxiety disorders found no completed suicides reported in the RCTs reviewed.There have been warnings about the risks associated with using antidepressants in children. See review on depression in children and adolescents.

Comment

Two additonal RCTs add support to the results of the RCT comparing fluvoxamine versus placebo,with the findings that fluvoxamine reduced somatic symptoms (for example, muscle tension and stomach aches), and sleep-related problems in children with anxiety disorders. Despite the positive findings with SSRIs to date, it is important to note that most studies investigating pharmacological effects on childhood anxiety have excluded participants with comorbid disorders such as depression. This may restrict the generalisability of the results.

Substantive changes

Antidepressants in children and adolescents New option added. One systematic reviewand two subsequent RCTs included. Antidepressants in children and adolescents categorised as Trade-off between benefits and harms.

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Antipsychotics in children and adolescents

Summary

We found no systematic review or RCTs on the effects of antipsychotics in children or adolescents with generalised anxiety disorder.

Benefits

We found no systematic review or RCTs on the effects of antipsychotics in children or adolescents with generalised anxiety disorder.

Harms

We found no RCTs.

Comment

None.

Substantive changes

Antipsychotics in children and adolescents New option added. No RCTs identified. Antipsychotics in children and adolescents categorised as Unknown effectiverness.

BMJ Clin Evid. 2007 Nov 20;2007:1002.

Pregabalin in children and adolescents

Summary

We found no systematic review or RCTs on the effects of pregabalin in children or adolescents with generalised anxiety disorder.

Benefits

We found no systematic review or RCTs on the effects of pregabalin in children or adolescents with generalised anxiety disorder.

Harms

We found no RCTs.

Comment

None.

Substantive changes

Pregabalin in children and adolescents New option added. No RCTs found. Pregabalin in children and adolescents categorised as Unknown effectiveness.

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PERMALINK

Generalised anxiety disorder

Christopher K Gale, MBChB, FRANZCP

Jane Millichamp

Roles

Key Points

About this condition

Definition

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Glossary

Disclaimer

Contributor Information

References

CBT in adults

Summary

Benefits

Table 1.

CBT versus waiting list control or non-specific therapies:

CBT versus psycho-dynamic therapy:

CBT versus supportive therapy:

Cognitive therapy versus behavioural therapy (including applied relaxation):

CBT versus non-specific therapy in benzodiazepine discontinuation:

Harms

Comment

Substantive changes

Applied relaxation in adults

Summary

Benefits

Applied relaxation versus placebo or no treatment:

Applied relaxation versus other psychological treatments:

Harms

Applied relaxation versus other psychological treatments:

Comment

Substantive changes

Benzodiazepines in adults

Summary

Benefits

Benzodiazepines versus placebo:

Benzodiazepines versus each other:

Long-term treatment:

Benzodiazepines versus buspirone:

Benzodiazepines versus hydroxyzine:

Benzodiazepines versus abecarnil:

Benzodiazepines versus antidepressants:

Benzodiazepines versus pregabalin:

Harms

Benzodiazepines versus placebo:

Dependence and sedation:

Memory:

Road traffic accidents:

Pregnancy and breast feeding:

Other:

Benzodiazepines versus buspirone:

Benzodiazepines versus hydroxyzine:

Benzodiazepines versus abecarnil:

Benzodiazepines versus antidepressants:

Benzodiazepines versus pregabalin:

Comment

Substantive changes

Buspirone in adults

Summary

Benefits

Buspirone versus placebo:

Buspirone versus benzodiazepines:

Buspirone versus antidepressants:

Buspirone versus hydroxyzine:

Harms

Buspirone versus placebo:

Buspirone versus benzodiazepines:

Buspirone versus hydroxyzine:

Comment

Benzodiazepines versus placebo or buspirone:

Substantive changes

Hydroxyzine in adults

Summary