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. 2011 Oct 27;2011:1002.

Generalised anxiety disorder

Christopher K Gale 1,#, Jane Millichamp 2,#
PMCID: PMC3275153  PMID: 22030083

Abstract

Introduction

Up to one in five people may have generalised anxiety disorder (GAD) at some point, 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.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for GAD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2011 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 74 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: abecarnil, antidepressants (duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, opipramol, paroxetine, sertraline, and venlafaxine), antipsychotic drugs (trifluoperazine), applied relaxation, benzodiazepines, buspirone, cognitive behavioural therapy, hydroxyzine, and pregabalin.

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 1 in 20 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 compared with waiting list control, treatment as usual, or enhanced usual care.

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

Applied relaxation may be as effective as CBT, but we found insufficient RCT evidence about applied relaxation compared with no treatment.

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 trials 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 RCT 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 adverse effects including drowsiness, and movement disorders.

We don't know whether abecarnil reduces anxiety as the RCTs we found reported inconsistent results.

In children and adolescents:

CBT improves symptoms compared with waiting list control or active control.

  • Most RCTs of CBT in children and adolescents have included other anxiety disorders.

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

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

Clinical context

About this condition

Definition

Generalised anxiety disorder (GAD) is defined as excessive worry and tension about everyday 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.[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 by panic attacks.[1] 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.[2] It also found that people with GAD had low overall life satisfaction, and some impairment in ability to fulfil roles, social tasks, or both.[2]

Incidence/ Prevalence

The most recent community surveys have used a newer version of the Composite International Diagnostic Interview (CIDI), which 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).[3] 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%).[4] In this survey, people aged >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%.[4] An observational survey in the UK in 2000 of people aged 16 to 74 years used the Clinical Interview Schedule-Revised (CIS-R), followed by a Schedules for Clinical Assessment in Neuropsychiatry [SCAN] interview of a stratified sample.[5] The survey estimated that 4.7% of people had GAD (men: 4.6%; women: 4.8%). A survey of children and adolescents aged 5 to 16 years in the UK in 2004, which used a similar methodology, estimated that 0.7% had GAD (boys: 0.6%; girls: 0.8%).[6] In the European survey of adults, 76% of those people who had more than one mental disorder for 12 months had GAD.[3] 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).[3] Another observational survey in 2004 found that people with GAD were also more likely to have physical health problems.[7] In one systematic review (search date 2006), people with GAD had a significantly decreased quality of life (effect size [6 studies, 248 people, P <0.01).[8] 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.[9]

Aetiology/ Risk factors

GAD is believed to be associated with an increase in the number of minor life events, independent of demographic factors;[10] however, this finding is also common in people with other diagnoses.[11] One non-systematic review (5 case-control studies) of psychological sequelae to civilian trauma found that rates of GAD reported in 4 of the 5 studies were significantly increased compared with a control population (RR 3.3, 95% CI 2.0 to 5.5).[12] 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).[13] 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).[14] 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.[15]

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.[16] The Harvard–Brown anxiety research programme reported 5-year follow-up of 167 people with GAD.[17] 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

Symptom severity: as measured by symptom scores on continuous rating scales. 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 for symptom assessment 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. Quality of life. Adverse effects of treatment.

Methods

Clinical Evidence search and appraisal May 2011. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2011, Embase 1980 to May 2011, and The Cochrane Database of Systematic Reviews, 2011, Issue 2 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). 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 contributor for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs and RCTs in any language, at least single blinded, and containing >20 individuals of whom >80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied applying the same study design criteria for inclusion as we did for benefits. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the 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 comorbid condition. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Generalised anxiety disorder.

Important outcomes Quality of life, Symptom severity
Studies (Participants) Outcome Comparison Type of evidence Quality Consistency Directness Effect size GRADE Comment
What are the effects of treatments for generalised anxiety disorder in adults?
at least 23 (at least 871) Symptom severity CBT versus waiting list control or non-specific therapies 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and for poor-quality RCTs in systematic reviews (poor follow-up, mixed populations, no intention-to-treat analyses in some RCTs)
2 (167) Symptom severity CBT versus psychodynamic therapy 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
7 (332) Symptom severity CBT versus supportive therapy 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (at least 341) Symptom severity Cognitive therapy versus behavioural therapy (including applied relaxation) 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (61) Symptom severity CBT versus non-specific therapy in benzodiazepine discontinuation 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
1 (42) Symptom severity Applied relaxation versus placebo or no treatment 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for population with comorbid conditions
54 (at least 2044) Symptom severity Benzodiazepines versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (185) Symptom severity Benzodiazepines versus each other 4 –2 0 0 0 Low Quality points deducted for sparse data and incomplete reporting of results
2 (61) Symptom severity Benzodiazepines versus CBT 4 –3 0 0 0 Very low Quality points deducted for sparse data, incomplete reporting of results, and no significance assessments
24 (at least 273) Symptom severity Buspirone versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
4 (338) Symptom severity Buspirone versus benzodiazepines 4 –2 –1 0 0 Very low Quality points deducted for incomplete reporting of results and methodological flaws (uncertainty about diagnosis). Consistency point deducted for conflicting results
at least 4 (at least 417) Symptom severity Hydroxyzine versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
2 (327) Symptom severity Hydroxyzine versus benzodiazepines 4 –2 0 0 0 Low Quality points deducted for incomplete reporting of results and no intention-to-treat analysis in the larger RCT
1 (163) Symptom severity Hydroxyzine versus buspirone 4 –1 0 0 0 Moderate Quality point deducted for sparse data
2 (439) Symptom severity Abecarnil versus placebo 4 –2 0 0 0 Low Quality points deducted for no intention-to-treat analysis and incomplete reporting of results
1 (310) Symptom severity Abecarnil versus benzodiazepines 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
7 (2418) Symptom severity Any antidepressant versus placebo 4 –1 0 0 0 Moderate Quality point deducted for no intention-to-treat analysis in some trials
4 (at least 419) Symptom severity Duloxetine versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
8 (2667) Symptom severity Escitalopram versus placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (207) Symptom severity Opipramol versus placebo 4 0 0 0 0 High
3 (1163) Symptom severity Paroxetine versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
3 (1084) Symptom severity Sertraline versus placebo 4 –1 0 0 0 Moderate Quality point deducted for not describing method of randomisation in 1 RCT
1 (373) Quality of life Sertraline versus placebo 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
11 (at least 2949) Symptom severity Venlafaxine versus placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
1 (544) Quality of life Venlafaxine versus placebo 4 –1 +1 0 0 High Quality point deducted for lack of significance assessment. Consistency point added for dose response
5 (583) Symptom severity Antidepressants versus each other 4 –1 –1 0 0 Low Quality point deducted for methodological weaknesses (not reporting method of randomisation, and short follow-up). Consistency point deducted for conflicting results
3 (479) Symptom severity Antidepressants versus benzodiazepines 4 0 0 –1 0 Moderate Directness point deducted for no direct comparison between groups in 1 RCT
1 (365) Symptom severity Antidepressants versus buspirone 4 –1 0 0 0 Moderate Quality point deducted for incomplete reporting of results
at least 6 (at least 2845) Symptom severity Antipsychotics versus placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
5 (at least 1260) Symptom severity Pregabalin versus placebo 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for different results with different doses
2 (725) Symptom severity Pregabalin versus benzodiazepines 4 –1 –1 0 0 Low Quality point deducted for incomplete reporting of results. Consistency point deducted for conflicting results
What are the effects of treatments for generalised anxiety disorder in children and adolescents?
11 (1125) Symptom severity CBT versus waiting list control or active control 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of children with other disorders
3 (357) Symptom severity Individual versus family or group CBT 4 –1 0 –1 0 Low Quality point deducted for low follow-up. Directness point deducted for inclusion of children with other disorders
9 (1448) Symptom severity Antidepressants versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of children with other disorders
4 (390) Quality of life Antidepressants versus placebo 4 –1 0 –1 0 Low Quality point deducted for incomplete reporting of results. Directness point deducted for inclusion of children with other disorders
1 (74) Symptom severity Fluoxetine versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for inclusion of children with other disorders
1 (128) Symptom severity Fluvoxamine versus placebo 4 –1 0 –1 0 Low Quality point deducted for sparse data. Directness point deducted for inclusion of children with other disorders
2 (231) Symptom severity Sertraline versus placebo 4 0 0 –1 0 Moderate Directness point deducted for inclusion of children with other disorders
1 (272) Symptom severity Antidepressants versus CBT 4 0 0 –1 0 Moderate Directness point deducted for inclusion of children with other disorders
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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

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 to 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.

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.

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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 School of Medicine, University of Otago, Dunedin, New Zealand.

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

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BMJ Clin Evid. 2011 Oct 27;2011:1002.

CBT in adults

Summary

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

CBT and applied relaxation may be equally effective at improving anxiety.

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

Benefits and harms

CBT versus waiting list control or non-specific therapies:

We found 6 systematic reviews (search dates 1996,[18] not reported,[19] 2006,[20] [21] [22] and 2007[23]) comparing CBT versus waiting list control (no treatment) or versus other psychotherapies in people with generalised anxiety disorder (GAD). Many of the RCTs were small and were not analysed on an intention-to-treat basis. Owing to crossover reporting between reviews, we report meta-analyses only from the more recent reviews. We found two subsequent RCTs.[24] [25]

Symptom severity

Compared with waiting list control or non-specific therapies CBT (using a combination of interventions, such as exposure, relaxation, systematic desensitisation, and cognitive restructuring) may be more effective than waiting list control or usual treatments (anxiety management, relaxation, supportive therapy, and non-directive psychotherapy) at improving symptoms of anxiety and at increasing clinical responses (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Anxiety
[23]
Systematic review		 95 people
2 RCTs in this analysis		 Change in anxiety scale treatment duration not reported
with CBT
with non-directive therapy or supportive therapy
Absolute numbers not reported
P = 0.03 		Effect size not calculated CBT
[22]
Systematic review		 146 people aged >60 years
4 RCTs in this analysis		 Change in anxiety scale treatment duration not specified
with CBT
with waiting list control
Absolute numbers not reported
SMD –0.44
95% CI –0.84 to –0.04
P = 0.03 		Effect size not calculated CBT
[22]
Systematic review		 243 people aged >60 years
5 RCTs in this analysis		 Change in anxiety scale treatment duration not specified
with CBT
with active control
Absolute numbers not reported
SMD –0.51
95% CI –0.81 to –0.21
P = 0.0009 		Effect size not calculated CBT
[21]
Systematic review		 Total number of people not reported
7 RCTs in this analysis		 Anxiety symptoms: all trials used Penn State Worry Questionnaire (PSWQ)
with CBT
with waiting list control or non-specific therapies (supportive therapy)
Absolute results not reported
Pooled effect size (CBT v control) 1.15
CI not reported
P <0.05
Measure of effect size not reported 		Effect size not calculated CBT
[24]
RCT		 134 older people (mean age 67 years) Mean change in worry severity (PSWQ) 3 months
7.7 with CBT
3.2 with enhanced usual care
P <0.001 		Effect size not calculated CBT
[24]
RCT		 134 older people (mean age 67 years) Mean change in anxiety (GAD Severity Scale [GADSS]) 3 months
2.8 with CBT
1.4 with enhanced usual care
P = 0.19 		Not significant
[24]
RCT		 134 older people (mean age 67 years) Mean change in anxiety severity (SIGH-A) 3 months
4.3 with CBT
3.0 with enhanced usual care
P = 0.23 		Not significant
[24]
RCT		 134 older people (mean age 67 years) Mean change in general mental health (short-form [SF]-12 mental component scale) 3 months
7.2 with CBT
3.6 with enhanced usual care
P = 0.008 		Effect size not calculated CBT
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Clinician Severity Rating 12 weeks
From 5.78 to 1.61 with CBT
From 5.90 to 4.78 with waiting list control
P <0.001 		Effect size not calculated CBT
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in PSWQ 12 weeks
From 61.65 to 51.13 with CBT
From 57.34 to 58.80 with waiting list control
P <0.001 		Effect size not calculated CBT
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Worry and Anxiety Questionnaire, Somatic Scale 12 weeks
From 21.13 to 17.74 with CBT
From 22.42 to 21.45 with waiting list control
P <0.005 		Effect size not calculated CBT
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in State Trait Anxiety Inventory, trait version 12 weeks
From 53.04 to 46.35 with CBT
From 52.06 to 48.98 with waiting list control
P <0.001 		Effect size not calculated CBT
Clinical response
[20]
Systematic review		 334 people
8 RCTs in this analysis		 Proportion of non-responders measured by clinician-rated composite measure or structured diagnostic interviews
54% with CBT
86% with waiting list control or treatment as usual
RR 0.64
95% CI 0.55 to 0.74 		Small effect size CBT
Open in a new tab

Quality of life

No data from the following reference on this outcome.[20] [21] [22] [23] [24] [25]

Adverse effects

No data from the following reference on this outcome.[20] [21] [22] [23] [24] [25]

CBT versus psychodynamic therapy:

We found one systematic review (search date 2006), which included one RCT comparing cognitive therapy plus anxiety management versus psychodynamic therapy.[20] We found one subsequent RCT.[26]

Symptom severity

Compared with psychodynamic therapy We don't know how CBT and psychodynamic therapy compare at improving symptoms of generalised anxiety disorder (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[20]
Systematic review		 110 people
Data from 1 RCT		 Response rate defined from State-Trait Anxiety Inventory (STAI-I) after therapy
28% with CBT plus anxiety management
7% with psychodynamic therapy
RR 0.77
95% CI 0.65 to 0.92 		Small effect size CBT plus anxiety management
[20]
Systematic review		 110 people
Data from 1 RCT		 Response rate defined from STAI-I 6 months
39% with CBT plus anxiety management
23% with psychodynamic therapy
RR 0.79
95% CI 0.62 to 1.01 		Not significant
[26]
RCT		 57 people Hamilton Anxiety Rating Scale (HAM-A) score 30 weeks
8.99 with CBT
9.15 with short-term psychodynamic therapy
P = 0.51 		Not significant
[26]
RCT		 57 people Penn State Worry Questionnaire score 30 weeks
7.32 with CBT
4.23 with short-term psychodynamic therapy
P = 0.03 		Effect size not calculated CBT
[26]
RCT		 57 people Beck Anxiety Inventory score 30 weeks
6.35 with CBT
6.20 with short-term psychodynamic therapy
P = 0.89 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[20] [26]

Adverse effects

No data from the following reference on this outcome.[20] [26]

CBT versus supportive therapy:

We found one systematic review (search date 2006, 7 RCTs) comparing CBT versus supportive therapy.[20] Many of the RCTs were small and were not analysed on an intention-to-treat basis.

Symptom severity

Compared with supportive therapy CBT and supportive therapy seem equally effective at improving clinical responses, but CBT seems more effective at improving anxiety symptoms at 6 months (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[20]
Systematic review		 332 people
6 RCTs in this analysis		 Response rate assessed through composite measure of anxiety severity (3 RCTs) and Hamilton Anxiety Rating Scale (HAM-A) (3 RCTs) post treatment
42% with cognitive therapy
28% with supportive therapy
Absolute numbers not reported
RR 0.86
95% CI 0.70 to 1.06 		Not significant
[20]
Systematic review		 332 people
6 RCTs in this analysis		 Response rate assessed through composite measure of anxiety severity (3 RCTs) and HAM-A (3 RCTs) 6 months
with cognitive therapy
with supportive therapy
Absolute numbers not reported
RR 0.79
95% CI 0.59 to 1.06 		Not significant
[20]
Systematic review		 235 people
6 RCTs in this analysis		 Anxiety symptoms post treatment
with cognitive therapy
with supportive therapy
Absolute numbers not reported
SMD –0.40
95% CI –0.66 to –0.14 		Effect size not calculated CBT
[20]
Systematic review		 97 people
3 RCTs in this analysis		 Anxiety symptoms 6 months
with cognitive therapy
with supportive therapy
Absolute numbers not reported
SMD –0.42
95% CI –0.83 to –0.02 		Effect size not calculated CBT
Open in a new tab

Quality of life

No data from the following reference on this outcome.[20]

Adverse effects

No data from the following reference on this outcome.[20]

Cognitive therapy versus behavioural therapy (including applied relaxation):

We found one systematic review (search date 2006, 5 RCTs), which pooled data.[20] 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. We found one additional[27] and one subsequent RCT.[25]

Symptom severity

Compared with behavioural therapy (including applied relaxation) Cognitive therapy may be more effective than behavioural therapy at improving response rates but not anxiety scores at 6 months. Cognitive therapy may be no more effective than applied relaxation at improving response rates or symptoms of anxiety (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[20]
Systematic review		 220 people
5 RCTs in this analysis		 Clinical response rates end of treatment
50% with cognitive therapy
31% with behavioural therapy
Absolute numbers not reported
RR 0.70
95% CI 0.56 to 0.87 		Small effect size cognitive therapy
[20]
Systematic review		 105 people
2 RCTs in this analysis		 Clinical response rates 6 months
58% with cognitive therapy
29% with behavioural therapy
Absolute numbers not reported
RR 0.56
95% CI 0.40 to 0.79 		Small effect size cognitive therapy
[20]
Systematic review		 131 people
4 RCTs in this analysis		 Mean anxiety symptom scores post treatment
with cognitive therapy
with behavioural therapy
Absolute numbers not reported
SMD –0.11
95% CI –0.59 to +0.30 		Not significant
[20]
Systematic review		 67 people
2 RCTs in this analysis		 Mean anxiety symptom scores 6 months
with cognitive therapy
with behavioural therapy
Absolute numbers not reported
SMD –0.11
95% CI –0.59 to +0.37 		Not significant
[20]
Systematic review		 36 people
Data from 1 RCT		 Clinical response post treatment
with cognitive therapy
with applied relaxation
Absolute numbers not reported
RR 0.60
95% CI 0.28 to 1.30
The review did not pool data on this comparison 		Not significant
[20]
Systematic review		 45 people
Data from 1 RCT		 Clinical response post treatment
with cognitive therapy
with applied relaxation
Absolute numbers not reported
RR 0.80
95% CI 0.51 to 1.26
The review did not pool data on this comparison 		Not significant
[20]
Systematic review		 40 people
Data from 1 RCT		 Clinical response post treatment
with cognitive therapy
with applied relaxation
Absolute numbers not reported
RR 0.29
95% CI 0.11 to 0.72
The review did not pool data on this comparison 		Moderate effect size cognitive therapy
[20]
Systematic review		 40 people
Data from 1 RCT		 Clinical response 6 months
with cognitive therapy
with applied relaxation
Absolute numbers not reported
RR 0.55
95% CI 0.25 to 1.19
The review did not pool data on this comparison 		Not significant
[27]
RCT
3-armed trial 		76 people Proportion of people no longer meeting criteria for GAD immediately after treatment
with cognitive therapy (with a behavioural component)
with cognitive therapy (without a behavioural component)
with applied relaxation with visualisation
Absolute numbers not reported
Reported no significant difference among groups 		Not significant
[27]
RCT
3-armed trial 		76 people Proportion of people no longer meeting criteria for GAD 24 months
with cognitive therapy (with a behavioural component)
with cognitive therapy (without a behavioural component)
with applied relaxation with visualisation
Absolute numbers not reported
Reported no significant difference among groups 		Not significant
[27]
RCT
3-armed trial 		76 people Anxiety measures (6) and depression measures (2) 24 months
with cognitive therapy (with a behavioural component)
with cognitive therapy (without a behavioural component)
with applied relaxation with visualisation
Absolute numbers not reported
Reported no significant difference among groups 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Clinician Severity Rating 12 weeks
From 5.78 to 1.61 with CBT
From 5.36 to 2.55 with applied relaxation
P value not reported
Reported as not significant 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Penn State Worry Questionnaire score 12 weeks
From 61.65 to 51.13 with CBT
From 58.01 to 52.16 with applied relaxation
P value not reported
Reported as not significant 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Worry and Anxiety Questionnaire, Somatic Scale 12 weeks
From 21.13 to 17.74 with CBT
From 20.82 to 17.91 with applied relaxation
P value not reported
Reported as not significant 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in State Trait Anxiety Inventory, trait version 12 weeks
From 53.04 to 46.35 with CBT
From 52.23 to 46.95 with applied relaxation
P value not reported
Reported as not significant 		Not significant
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Quality of life

No data from the following reference on this outcome.[20] [25] [27]

Adverse effects

No data from the following reference on this outcome.[20] [25] [27]

CBT versus non-specific therapy in benzodiazepine discontinuation:

We found one RCT comparing CBT plus medication tapering for benzodiazepine discontinuation versus non-specific psychological therapy (based on active listening) plus medication tapering.[28] Both groups had twelve 90-minute sessions of therapy.

Symptom severity

CBT plus medication tapering compared with non-specific therapy in benzodiazepine discontinuation CBT plus medication tapering may be more effective at increasing the proportion of people who discontinue benzodiazepines (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[28]
RCT		 61 people with GAD who had used benzodiazepines for at least 12 months Proportion of people who had stopped benzodiazepines at the end of the treatment
74% with CBT plus medication tapering
37% with non-specific psychological therapy plus medication tapering
Absolute numbers not reported
P = 0.003 		Effect size not calculated CBT plus medication tapering
[28]
RCT		 61 people with GAD who had used benzodiazepines for at least 12 months Proportion of people who had stopped benzodiazepines 12 months
65% with CBT plus medication tapering
30% with non-specific psychological therapy plus medication tapering
Absolute numbers not reported
P = 0.007 		Effect size not calculated CBT plus medication tapering
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Quality of life

No data from the following reference on this outcome.[28]

Adverse effects

No data from the following reference on this outcome.[28]

CBT versus drug treatment:

See option on benzodiazepines.

Further information on studies

The review noted that the RCTs were heterogeneous (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 <0.05 for either comparison).

Comment

None.

Substantive changes

CBT in adults New evidence added.[22] [23] [24] [25] [26] Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Applied relaxation in adults

Summary

Applied relaxation may be as effective as CBT at reducing anxiety, but we found RCT insufficient evidence about applied relaxation compared with no treatment.

Benefits and harms

Applied relaxation versus placebo or no treatment:

We found one RCT.[25] See also cognitive therapy versus behavioural therapy (including applied relaxation) in CBT option.

Symptom severity

Compared with no treatment We don't know whether applied relaxation is more effective at improving symptoms of anxiety (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Clinician Severity Rating 12 weeks
From 5.36 to 2.55 with applied relaxation
From 5.90 to 4.78 with waiting list control
P = 0.006 		Effect size not calculated applied relaxation
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Penn State Worry Questionnaire score 12 weeks
From 58.01 to 52.16 with applied relaxation
From 57.34 to 58.80 with waiting list control
P value not reported
Reported as not significant 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in Worry and Anxiety Questionnaire, Somatic Scale 12 weeks
From 20.82 to 17.91 with applied relaxation
From 22.42 to 21.45 with waiting list control
P value not reported
Reported as not significant 		Not significant
[25]
RCT
3-armed trial 		65 people in whom GAD was the primary diagnosis Change in State Trait Anxiety Inventory, trait version 12 weeks
From 52.23 to 46.95 with applied relaxation
From 52.06 to 48.98 with waiting list control
P value not reported
Reported as not significant 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[25]

Adverse effects

No data from the following reference on this outcome.[25]

Applied relaxation versus CBT:

See option on CBT.

Applied relaxation versus other psychological treatments:

See option on CBT.

Further information on studies

None.

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).[29]

Substantive changes

Applied relaxation in adults New evidence added.[25] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Benzodiazepines in adults

Summary

Benzodiazepines may reduce symptoms of anxiety in people with GAD, but can have unpleasant adverse effects, and most trials have been short term.

Benzodiazepines increase the risk of dependence, sedation, and accidents, and can cause adverse effects in neonates if used during pregnancy.

Benefits and harms

Benzodiazepines versus placebo:

We found two systematic reviews (search date 1996, 17 RCTs;[18] and search date 2002, 37 RCTs[30]). For further information on harms of benzodiazepines from observational studies, see comment.

Symptom severity

Compared with placebo Benzodiazepines seem more effective at reducing symptoms of anxiety at 2 to 9 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[18]
Systematic review		 2044 people
17 RCTs in this analysis		 Symptoms 2 to 9 weeks
with benzodiazepines
with placebo
Reported as significant
Pooled mean effect size 0.70
CI not reported
Measure of effect size not reported 		Effect size not calculated benzodiazepines
[30]
Systematic review		 People with anxiety disorders (total number of people not reported)
37 RCTs in this analysis		 Anxiety
with benzodiazepines
with placebo
Reported as significant
P value not reported 		Effect size not calculated benzodiazepines
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Quality of life

No data from the following reference on this outcome.[18] [30]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[31]
RCT
3-armed trial 		310 people
In review [30] 		Drowsiness
52% with diazepam (15–35 mg/day)
14% with placebo
Absolute numbers not reported
P <0.05 for diazepam v placebo 		Effect size not calculated placebo
[31]
RCT
3-armed trial 		310 people
In review [30] 		Dizziness
11% with diazepam (15–35 mg/day)
3% with placebo
Absolute numbers not reported
P <0.05 for diazepam v placebo 		Effect size not calculated placebo
[18]
Systematic review		 People with anxiety disorders
Data from 1 RCT		 Drowsiness
71% with diazepam
13% with placebo
Absolute numbers not reported
P = 0.001 		Effect size not calculated placebo
[18]
Systematic review		 People with anxiety disorders
Data from 1 RCT		 Dizziness
29% with diazepam
11% with placebo
Absolute numbers not reported
P = 0.001 		Effect size not calculated placebo
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Benzodiazepines versus each other:

We found two RCTs.[32] [33]

Symptom severity

Benzodiazepines compared with each other We don't know whether one benzodiazepine is more effective than the others at 3 to 5 weeks at improving Hamilton Anxiety Scale (HAM-A) or Clinical Global Impressions Scale (CGI) scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[32]
RCT		 121 people Hamilton Anxiety Scale (HAM-A) scores over 5 weeks
with sustained-release alprazolam
with bromazepam
Absolute results reported graphically
Reported as not significant 		Not significant
[32]
RCT		 121 people Clinical Global Impressions Scale (CGI) scores over 5 weeks
with sustained-release alprazolam
with bromazepam
Absolute results reported graphically
Reported as not significant 		Not significant
[33]
RCT		 64 people Proportion of people who had "highly improved" or "moderately improved" CGIS scores 3 weeks
with mexazolam
with alprazolam
Absolute results reported graphically
98% "highly improved"; 87% "moderately improved"
P >0.05 		Not significant
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Quality of life

No data from the following reference on this outcome.[32] [33]

Adverse effects

No data from the following reference on this outcome.[32] [33]

Benzodiazepines versus CBT:

We found one systematic review (search date not reported, 2 small RCTs).[34] The review did not perform a meta-analysis.

Symptom severity

Lorazepam compared with CBT We don't know how lorazepam and CBT compare at improving symptoms of generalised anxiety disorder (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[34]
Systematic review		 20 people
Data from 1 RCT		 Patient-rated improvement 4 weeks
with lorazepam
with CBT
Absolute numbers not reported
Significance not assessed
[34]
Systematic review		 41 people
Data from 1 RCT		 Patient-rated improvement 10 weeks
with lorazepam
with CBT
Absolute numbers not reported
Significance not assessed
[34]
Systematic review		 41 people
Data from 1 RCT		 Clinician-rated improvement 10 weeks
with lorazepam
with CBT
Absolute numbers not reported
Significance not assessed
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Quality of life

No data from the following reference on this outcome.[34]

Adverse effects

No data from the following reference on this outcome.[34]

Long-term treatment with benzodiazepines:

We found one systematic review (search date 1998, 8 RCTs, any benzodiazepine medication, >2 months' duration).[35] It found that the weak methods of the RCTs prevented firm conclusions being drawn.

Benzodiazepines versus buspirone:

See option on buspirone.

Benzodiazepines versus hydroxyzine:

See option on hydroxyzine.

Benzodiazepines versus abecarnil:

See option on abecarnil.

Benzodiazepines versus antidepressants:

See option on antidepressants.

Benzodiazepines versus pregabalin:

See option on pregabalin.

Further information on studies

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

Comment

Dependence and sedation:

One non-systematic review of the harms of benzodiazepines found that rebound anxiety on withdrawal was reported in 15% to 30% of people.[36] It also found a high risk of substance abuse and dependence with benzodiazepines.

Memory:

Thirty-one people with agoraphobia/panic disorder in an RCT comparing alprazolam versus placebo for 8 weeks were reviewed after 3.5 years.[37] 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.[38] 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 to 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% to 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 >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.[39] However, case reports in one non-systematic review suggested that benzodiazepines taken in late pregnancy may be associated with neonatal hypotonia and withdrawal syndrome.[40] Benzodiazepines are secreted in breast milk, and there have been reports of sedation and hypothermia in infants.[40]

Other precautions:

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.[41]

Substantive changes

Benzodiazepines in adults New evidence added.[34] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Buspirone in adults

Summary

Buspirone may reduce symptoms of anxiety in people with GAD, but can have unpleasant adverse effects, and most trials have been short term.

Buspirone may be less effective if used in people who have recently been taking benzodiazepines.

Benefits and harms

Buspirone versus placebo:

We found three systematic reviews (search date 1996, 9 RCTs;[18] search date 2002, 12 RCTs;[30] and search date 2005).[42]

Symptom severity

Compared with placebo Buspirone seems more effective at improving symptoms based on the Hamilton Anxiety Scale (HAM-A) or Clinical Global Impressions Scale (CGI) scores (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[18]
Systematic review		 People with anxiety disorders
9 RCTs in this analysis		 Symptoms 4 to 9 weeks
with buspirone
with placebo
Absolute results not reported
Reported as significant
CI and P value not reported 		Effect size not calculated buspirone
[30]
Systematic review		 People with anxiety disorders
12 RCTs in this analysis		 Symptoms
with buspirone
with placebo
Absolute results not reported
Reported as significant
Pooled mean effect size 0.39
CI not reported 		Effect size not calculated buspirone
[42]
Systematic review		 21 people
Data from 1 RCT		 Hamilton Anxiety Scale (HAM-A) score
with buspirone
with placebo
Absolute results not reported
WMD +0.4
95% CI –5.62 to +6.42 		Not significant
[42]
Systematic review		 38 people
Data from 1 RCT		 HAM-A score
with buspirone
with placebo
Absolute results not reported
WMD –7.52
95% CI –9.89 to –5.15 		Effect size not calculated buspirone
[42]
Systematic review		 52 people
Data from 1 RCT		 HAM-A score
with buspirone
with placebo
Absolute results not reported
WMD –3.73
95% CI –4.01 to –3.45 		Effect size not calculated buspirone
[42]
Systematic review		 162 people
Data from 1 RCT		 Clinical Global Impressions scale (CGI) much or very improved
with buspirone
with placebo
Absolute results not reported
RR 1.48
95% CI 1.01 to 2.17
P = 0.04 		Small effect size buspirone
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Quality of life

No data from the following reference on this outcome.[18] [30] [42]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[43]
RCT		 240 people
In review [30] 		Proportion of people with nausea
27/80 (34%) with buspirone
11/82 (13%) with placebo
RR 2.5
95% CI 1.3 to 4.7
NNH 5
95% CI 4 to 14 		Moderate effect size placebo
[43]
RCT		 240 people
In review [30] 		Proportion of people with dizziness
51/80 (64%) with buspirone
10/82 (12%) with placebo
RR 5.2
95% CI 2.9 to 9.6
NNH 2
95% CI 2 to 3 		Large effect size placebo
[43]
RCT		 240 people
In review [30] 		Proportion of people with somnolence
15/80 (19%) with buspirone
6/82 (7%) with placebo
RR 2.6
95% CI 1.0 to 6.3
NNH 9
95% CI 5 to 104 		Moderate effect size placebo
[42]
Systematic review		 635 people
Data from 1 RCT		 Dizziness
with buspirone
with placebo
Absolute results not reported
RR 3.18
95% CI 1.82 to 5.56 		Moderate effect size placebo
[42]
Systematic review		 429 people
Data from 1 RCT		 Nausea
with buspirone
with placebo
Absolute results not reported
RR 2.16
95% CI 1.14 to 4.10 		Moderate effect size placebo
Open in a new tab

No data from the following reference on this outcome.[18]

Buspirone versus benzodiazepines:

We found two systematic reviews (search dates 1996[18] and 2005[42]). The first systematic review[18] found one RCT, which compared three interventions: buspirone, diazepam, and placebo.[43] The other 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 RCTs.[42]

Symptom severity

Compared with benzodiazepines We don't know whether buspirone is more effective at improving symptoms at 6 weeks (very low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[43]
RCT
3-armed trial 		240 people
In review [18] 		Proportion of people who responded (at least 40% reduction in Hamilton Anxiety Scale [HAM-A] score) 6 weeks
54% with buspirone
61% with diazepam
Absolute numbers not reported
P value not reported
[42]
Systematic review
3-armed trial 		60 people
Data from 1 RCT		 HAM-A score
with buspirone
with alprazolam
Absolute results not reported
WMD (alprazolam v buspirone) 1.1
95% CI 0.28 to 1.92 		Effect size not calculated alprazolam
[42]
Systematic review
3-armed trial 		60 people
Data from 1 RCT		 HAM-A score
with lorazepam
with buspirone
Absolute results not reported
WMD (lorazepam v buspirone) 1.1
95% CI 0.29 to 1.91 		Effect size not calculated lorazepam
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Quality of life

No data from the following reference on this outcome.[18] [42] [43]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[43]
RCT
3-armed trial 		240 people
In review [18] 		Adverse effects
with buspirone
with diazepam
Absolute numbers not reported
Significance not assessed
[42]
Systematic review		 People with anxiety disorders Drowsiness
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.29
95% CI 0.21 to 0.41 		Moderate effect size buspirone
[42]
Systematic review		 People with anxiety disorders Fatigue
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.24
95% CI 0.13 to 0.45 		Moderate effect size buspirone
[42]
Systematic review		 People with anxiety disorders Nervousness
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.17
95% CI 0.06 to 0.47 		Large effect size buspirone
[42]
Systematic review		 People with anxiety disorders Depression
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.22
95% CI 0.12 to 0.39 		Moderate effect size buspirone
[42]
Systematic review		 People with anxiety disorders Insomnia
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.14
95% CI 0.03 to 0.63 		Large effect size buspirone
[42]
Systematic review		 People with anxiety disorders Sleep problems
with buspirone
with benzodiazepines
Absolute results not reported
RR 0.25
95% CI 0.08 to 0.81 		Moderate effect size buspirone
[42]
Systematic review		 People with anxiety disorders Nausea
with buspirone
with benzodiazepines
Absolute results not reported
RR 2.84
95% CI 1.14 to 7.09 		Moderate effect size benzodiazepines
[42]
Systematic review		 People with anxiety disorders Dizziness
with buspirone
with benzodiazepines
Absolute results not reported
RR 2.28
95% CI 1.15 to 4.54 		Moderate effect size benzodiazepines
Open in a new tab

Buspirone versus antidepressants:

See option on antidepressants.

Buspirone versus hydroxyzine:

See option on hydroxyzine.

Further information on studies

None.

Comment

Benzodiazepines versus placebo or buspirone:

Adverse effects

One systematic review of jitteriness/anxiety syndrome (search date 2006)[44] identified a case report of anxiety/jitteriness syndrome in a patient with GAD taking buspirone.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Hydroxyzine in adults

Summary

Hydroxyzine may reduce symptoms of anxiety in people with GAD, but it can have unpleasant adverse effects, and most trials have been short term.

Benefits and harms

Hydroxyzine versus placebo:

We found one systematic review (search date 2010, 5 RCTs).[45]

Symptom severity

Compared with placebo Hydroxyzine seems more effective at improving symptoms and response rates (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[45]
Systematic review		 417 people
4 RCTs in this analysis		 Proportion of people who did not show a response
83/219 (38%) with hydroxyzine
123/198 (62%) with placebo
OR 0.30
95% CI 0.15 to 0.58
P <0.0004 		Effect size not calculated hydroxyzine
[45]
Systematic review		 381 people
2 RCTs in this analysis		 Difference in efficacy scale
with hydroxyzine
with placebo
Absolute numbers not reported
SMD –0.42
95% CI –0.62 to –0.21
P <0.00006 		Effect size not calculated hydroxyzine
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Quality of life

No data from the following reference on this outcome.[45]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[45]
Systematic review		 584 people
4 RCTs in this analysis		 Proportion of people reporting adverse effects
127/301 (42%) with hydroxyzine
99/283 (35%) with placebo
OR 1.49
95% CI 0.92 to 2.40
P = 0.1 		Not significant
[45]
Systematic review		 218 people
Data from 1 RCT		 Withdrawal symptoms
42% with hydroxyzine
35% with placebo
Absolute results not reported
OR 1.43
95% CI 0.62 to 3.30 		Not significant
Open in a new tab

Hydroxyzine versus benzodiazepines:

We found one systematic review (search date 2010, 5 RCTs).[45]

Symptom severity

Compared with benzodiazepines Hydroxyzine and benzodiazepines may be equally effective at improving response and reducing symptom severity (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[45]
Systematic review		 106 people
Data from 1 RCT		 Proportion of people who did not show a response
22/55 (40%) with hydroxyzine
24/51 (47%) with chlordiazepoxide
OR 0.75
95% CI 0.35 to 1.62 		Not significant
[45]
Systematic review		 221 people
Data from 1 RCT		 Difference in efficacy scale
with hydroxyzine
with bromazepam
Absolute numbers not reported
SMD –0.01
95% CI –0.27 to +0.26 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[45]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[45]
Systematic review		 327 people
2 RCTs in this analysis		 Proportion of people reporting adverse effects
34/160 (21%) with hydroxyzine
30/167 (18%) with benzodiazepines
OR 1.20
95% CI 0.69 to 2.09
P = 0.52 		Not significant
[45]
Systematic review		 221 people
Data from 1 RCT		 Proportion of people reporting withdrawal symptoms
with hydroxyzine
with benzodiazepines
Absolute numbers not reported
OR 0.84
95% CI 0.39 to 1.78 		Not significant
Open in a new tab

Hydroxyzine versus buspirone:

We found one systematic review (search date 2010, 1 RCT).[45]

Symptom severity

Hydroxyzine compared with buspirone Hydroxyzine and buspirone seem equally effective at improving response (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[45]
Systematic review		 163 people
Data from 1 RCT		 Proportion of people who failed to show a response
47/81 (58%) with hydroxyzine
53/82 (65%) with buspirone
OR 0.76
95% CI 0.40 to 1.42 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[45]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[45]
Systematic review		 163 people
Data from 1 RCT		 Proportion of people reporting adverse effects
32/81 (40%) with hydroxyzine
31/82 (38%) with buspirone
OR 1.07
95% CI 0.57 to 2.02 		Not significant
Open in a new tab

Further information on studies

The review defined response as a reduction of at least 50% on the Hamilton Anxiety Scale (HAM-A) at follow-up. When HAM-A and other scales were not available, the review considered as response a Clinical Global Impressions Scale (CGI)-S (severity) criteria score of 1, 2, or 3, and CGI-I (improvement) criteria score of 1 or 2. If no scale was provided, the review accepted any definition of outcome from the authors. Adverse effects The review found an association between hydroxyzine and increased sleepiness and drowsiness (OR 1.74, 95% CI 0.86 to 3.53).

Comment

There have been case reports of cutaneous drug eruptions[46] and supraventricular tachycardia in a child associated with use of hydroxyzine.[47] In overdose, catatonia has been reported.[48] A neonatal withdrawal syndrome involving seizures has been described in one case report.[49]

Substantive changes

Hydroxyzine in adults New evidence added.[45] Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Abecarnil in adults

Summary

We don't know whether abecarnil reduces anxiety as the RCTs we found reported inconsistent results.

Benefits and harms

Abecarnil versus placebo:

We found one systematic review (search date 2002, 4 RCTs)[30] and two multicentre RCTs of abecarnil.[50] [31] The review did not report results for abecarnil versus placebo separately.[30] The first RCT compared 3 weeks of treatment with abecarnil in three separate dose regimens (3–9 mg/day, 7.5–15 mg/day, and 15–30 mg/day) versus placebo.[50] Within each group the dose was escalated from the minimum to the maximum over the length of the trial. The second RCT compared three interventions: abecarnil 7.5 mg to 17.5 mg daily, diazepam 15 mg to 35 mg daily, and placebo.[31]

Symptom severity

Compared with placebo We don't know whether abecarnil is more effective at reducing Hamilton Anxiety Scale (HAM-A) scores by 50% (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[50]
RCT
4-armed trial 		129 people 50% reduction in Hamilton Anxiety Scale (HAM-A) score
19/31 (61%) with abecarnil (3–9 mg/day)
8/26 (31%) with placebo
RR 1.99
95% CI 1.05 to 3.78 		Small effect size abecarnil
[50]
RCT
4-armed trial 		129 people 50% reduction in HAM-A score
with abecarnil (7.5–15 mg/day and 15–30 mg/day)
with placebo
Reported no significant difference between higher doses of abecarnil and placebo 		Not significant
[31]
RCT
3-armed trial 		310 people Proportion of people with moderate improvement on the Clinical Global Impressions Scale (CGI) scores at 6 weeks
62% with abecarnil (7.5–17.5 mg/day)
56% with placebo
Reported no significant difference between abecarnil and placebo
P value not reported 		Not significant
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Quality of life

No data from the following reference on this outcome.[31] [50]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[50]
RCT
4-armed trial 		129 people Fatigue
4/32 (13%) with abecarnil (3–9 mg/day)
0/28 (0%) with placebo
Significance not assessed
[50]
RCT
4-armed trial 		129 people Equilibrium loss
2/32 (6%) with abecarnil (3–9 mg/day)
0/28 (0%) with placebo
Significance not assessed
[50]
RCT
4-armed trial 		129 people Drowsiness
10/32 (31%) with abecarnil (3–9 mg/day)
4/28 (14%) with placebo
Significance not assessed
[50]
RCT
4-armed trial 		129 people Proportion of people experiencing at least 1 adverse effect
62% with abecarnil (15–30 mg/day)
51% with abecarnil (7.5–15 mg/day)
22% with abecarnil (3–9 mg/day)
21% with placebo
Absolute numbers not reported
Significance not assessed
[50]
RCT
4-armed trial 		129 people 12/34 (35%) people Proportion of people who withdrew from treatment
12/34 (35%) with abecarnil (15–30 mg/day)
4/35 (11%) with abecarnil (7.5–15 mg/day)
1/32 (3%) with abecarnil (3–9 mg/day)
2/28 (7%) with placebo
Significance not assessed
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No data from the following reference on this outcome.[31]

Abecarnil versus benzodiazepines:

We found one RCT (310 people) comparing three interventions: abecarnil 7.5 mg to 17.5 mg daily, diazepam 15 mg to 35 mg daily, and placebo.[31]

Symptom severity

Compared with benzodiazepines Abecarnil and benzodiazepines seem equally effective at 6 weeks at increasing the number of people with a moderate improvement on Clinical Global Impressions Scale (CGI) scores (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[31]
RCT
3-armed trial 		310 people Proportion of people with moderate improvement on the Clinical Global Impressions Scale (CGI) scores at 6 weeks
62% with abecarnil (7.5–17.5 mg/day)
73% with diazepam (15–35 mg/day)
Reported no significant difference between abecarnil and diazepam
P value not reported 		Not significant
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Quality of life

No data from the following reference on this outcome.[31]

Adverse effects

No data from the following reference on this outcome.[31]

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Antidepressants in adults

Summary

Antidepressants (imipramine, duloxetine, 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 RCT found limited evidence of an increased benefit with escitalopram compared with paroxetine.

Benefits and harms

Any antidepressant versus placebo:

We found two systematic reviews (search dates 2002[51] and 2008[52]). The second review assessed relapse prevention.[52] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Any antidepressant compared with placebo Antidepressants (imipramine, paroxetine, and venlafaxine) seem more effective at 4 to 28 weeks at increasing response rates and at reducing relapse in people who have responded to treatment (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[51]
Systematic review		 1056 people
4 RCTs in this analysis		 Non-response rate 8 to 28 weeks
277/606 (46%) with antidepressants (imipramine, paroxetine, and venlafaxine)
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 		Small effect size antidepressants
[53]
RCT		 230 people
In review [51] 		Proportion of people with participant-assessed global improvement 8 weeks
73% with imipramine
67% with trazodone
66% with diazepam
39% with placebo
P <0.026 for any drug v placebo
Results not analysed by intention to treat 		Effect size not calculated antidepressants
[52]
Systematic review		 1342 people
3 RCTs in this analysis		 Proportion of people who relapsed after responding to treatment 6 months
93/664 (14%) with continuation of antidepressants
304/678 (45%) with placebo
OR 0.2
95% CI 0.15 to 0.26
NNT 3
95% CI 2.86 to 3.85 		Moderate effect size antidepressants
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Quality of life

No data from the following reference on this outcome.[51] [52] [53]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[53]
RCT		 People with anxiety disorders
In review [51] 		Adverse effects
with antidepressants
with placebo
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No data from the following reference on this outcome.[52]

Duloxetine versus placebo:

We found one systematic review (search date 2009, 5 RCTs).[54] We also report additional data separately from one RCT identified by the review, which was not included in the meta-analysis.[55]

Symptom severity

Compared with placebo Duloxetine seems more effective at reducing symptom severity (Sheehan Disability Scale) at 9 to 10 weeks and at reducing the proportion of people who relapse after responding to treatment (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[54]
Systematic review		 Number of people not reported
3 RCTs in this analysis		 Proportion of people with normalised Sheehan Disability Scale score 9 to 10 weeks
47% with duloxetine
28% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated duloxetine
[55]
RCT		 419 people who had responded to duloxetine in the first phase of a trial
In review [54] 		Proportion of people who relapsed after response 26 weeks
28/204 (14%) with duloxetine (60–120 mg/day)
84/201 (42%) with placebo
P <0.001 		Effect size not calculated duloxetine 60 mg to 120 mg
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Quality of life

No data from the following reference on this outcome.[54] [55]

Adverse effects

No data from the following reference on this outcome.[54] [55]

Escitalopram versus placebo:

We found 5 RCTs[56] [57] [58] [59] [60] and one report of pooled data from three RCTs comparing escitalopram versus placebo.[61] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Compared with placebo Escitalopram may be more effective at increasing remission and response rates at 8 to 12 weeks, and at reducing relapses and increasing time to relapse (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[56]
RCT		 315 people Remission (defined as a score of 7 or less on Hamilton Anxiety Scale [HAM-A]) 8 weeks
36% with escitalopram (10–20 mg/day)
16% with placebo
Absolute numbers not reported
P <0.01
Mean difference 3.9
95% CI 1.7 to 6.0 		Effect size not calculated escitalopram
[56]
RCT		 315 people Response rate (Clinical Global Impressions Scale [CGI] score of 1 or 2) 8 weeks
58% with escitalopram (10–20 mg/day)
38% with placebo
Absolute numbers not reported
P = 0.01 		Effect size not calculated escitalopram
[57]
RCT
5-armed trial 		681 people Mean HAM-A scores 12 weeks
–15.49 with escitalopram (5 mg/day)
–14.2 with placebo
P = 0.165 for escitalopram 5 mg v placebo 		Not significant
[57]
RCT
5-armed trial 		681 people Mean HAM-A scores 12 weeks
–16.8 with escitalopram (10 mg/day)
–14.2 with placebo
P = 0.006 for escitalopram 10 mg v placebo 		Effect size not calculated escitalopram
[57]
RCT
5-armed trial 		681 people Mean HAM-A scores 12 weeks
–16.4 with escitalopram (20 mg/day)
–14.2 with placebo
P = 0.022 for escitalopram 20 mg v placebo 		Effect size not calculated escitalopram
[57]
RCT
5-armed trial 		681 people Remission (defined as a HAM-A score <7) 12 weeks
with escitalopram (5 mg/day)
with escitalopram (10 mg/day)
with escitalopram (20 mg/day)
with placebo
Absolute numbers not reported
P <0.05 (all doses of escitalopram v placebo) 		Effect size not calculated escitalopram
[61]
Non-systematic review		 856 people
3 RCTs in this analysis		 Remission (defined as a HAM-A score <7) 8 weeks
5.8 with escitalopram
3.9 with placebo
P <0.001 		Effect size not calculated escitalopram
[61]
Non-systematic review		 856 people
3 RCTs in this analysis		 Mean improvement in HAM-A somatic anxiety subscale from baseline 8 weeks
4.3 with escitalopram
3.7 with placebo
P = 0.02 		Effect size not calculated escitalopram
[61]
Non-systematic review		 856 people
3 RCTs in this analysis		 Rates of HAM-A response (defined as at least 50% improvement in mean HAM-A score) 8 weeks
48% with escitalopram
29% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated escitalopram
[61]
Non-systematic review		 856 people
3 RCTs in this analysis		 Rates of CGI response (defined as CGI score of 1 or 2 [much or very much improved] plus remission [HAM-A score of 7 or less]) 8 weeks
52% with escitalopram
37% with placebo
Absolute numbers not reported
P <0.001 		Effect size not calculated escitalopram
[59]
RCT
3-armed trial 		392 people Mean difference in HAM-A 8 weeks
with escitalopram
with placebo
Absolute numbers not reported
Mean difference –1.52
P = 0.09 		Not significant
[58]
RCT		 375 people who had responded to escitalopram and had a HAM-A score of 10 or less Proportion of people who had relapsed (defined as a HAM-A score of 15 or above) 24 weeks
34/187 (18%) with continued escitalopram (20 mg/day)
98/188 (52%) with placebo
P <0.001 		Effect size not calculated escitalopram
[58]
RCT		 375 people who had responded to escitalopram and had a HAM-A score of 10 or less Time to relapse (defined as a HAM-A score of 15 or above)
with continued escitalopram (20 mg/day)
with placebo
Absolute results reported graphically
P <0.001 		Effect size not calculated escitalopram
[60]
RCT		 177 people aged >60 years Proportion of people responding (CGI) 12 weeks
57% with escitalopram
45% with placebo
Absolute numbers not reported
P = 0.11 		Not significant
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Quality of life

No data from the following reference on this outcome.[56] [57] [58] [59] [60] [61]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[56]
RCT		 315 people Headache
23% with escitalopram
18% with placebo
Absolute numbers not reported
[56]
RCT		 315 people Nausea
19% with escitalopram
9% with placebo
Absolute numbers not reported
[56]
RCT		 315 people Somnolence
12% with escitalopram
6% with placebo
Absolute numbers not reported
[56]
RCT		 315 people Upper respiratory tract infection
11% with escitalopram
7% with placebo
Absolute numbers not reported
[57]
RCT
5-armed trial 		681 people Anorgasmia over 12 weeks
9/139 (7%) with escitalopram (20 mg/day)
6/136 (4%) with escitalopram (10 mg/day)
0/139 (0%) with placebo
P <0.05 escitalopram v placebo 		Effect size not calculated placebo
[57]
RCT
5-armed trial 		681 people Insomnia
10% with escitalopram or paroxetine
2% with placebo
Absolute numbers not reported
[57]
RCT
5-armed trial 		681 people Proportion of people reporting fatigue
10% with escitalopram (10 mg/day)
17% with escitalopram (20 mg/day)
3% with placebo
Absolute numbers not reported
P <0.05 escitalopram v placebo 		Effect size not calculated placebo
[57]
RCT
5-armed trial 		681 people Diarrhoea
9.7% with escitalopram (5 mg/day)
9.6% with escitalopram (10 mg/day)
9.8% with escitalopram (20 mg/day)
2.9% with placebo
Absolute numbers not reported
P <0.05 escitalopram v placebo 		Effect size not calculated placebo
[59]
RCT
3-armed trial 		392 people Adverse effects 8 weeks
with escitalopram
with placebo
Absolute numbers not reported
P <0.05 		Effect size not calculated placebo
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No data from the following reference on this outcome.[58] [60] [61]

Opipramol versus placebo:

We found one systematic review[30] (search date 2002), which found one RCT.[62] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Compared with placebo Opipramol is more effective at increasing response rates at 28 days (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Response rate
[62]
RCT
3-armed trial 		318 people Response rate (defined as Clinical Global Impressions Scale [CGI] score of <2) 28 days
63/100 (63%) with opipramol
50/107 (47%) with placebo
RR 1.35
95% CI 1.05 to 1.69
NNT 7
95% CI 1 to 26 		Small effect size opipramol
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Quality of life

No data from the following reference on this outcome.[62]

Adverse effects

No data from the following reference on this outcome.[62]

Paroxetine versus placebo:

We found one systematic review[51] (search date 2002, 8 RCTs), which identified one RCT. We also found one additional RCT[63] and one subsequent multi-arm RCT.[57] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Paroxetine compared with placebo Paroxetine seems more effective than placebo at improving responses (measured as lower Clinical Global Impressions Scale [CGI] scores) at 4 to 10 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[51]
Systematic review		 324 people
Data from 1 RCT		 Non-treatment response (measured using Clinical Global Impressions Scale [CGI] scores, Hamilton Anxiety Scale [HAM-A] scores, and Sheehan Disability Scale scores) 8 weeks
with paroxetine
with placebo
Absolute results not reported
RR 0.72
95% CI 0.56 to 0.92
NNT 7
95% CI 4 to 25 		Small effect size paroxetine
[63]
RCT
3-armed trial 		565 people Response (defined as CGI scores 2 or less) 8 weeks
116/188 (62%) with paroxetine (20 mg/day)
82/180 (45%) with placebo
RR 1.36
95% CI 1.11 to 1.64
NNT 6
95% CI 4 to 13 		Small effect size paroxetine (20 mg/day)
[63]
RCT
3-armed trial 		565 people Response (defined as CGI scores 2 or less) 8 weeks
134/197 (68%) with paroxetine (40 mg/day)
82/180 (45%) with placebo
RR 1.49
95% CI 1.24 to 1.679
NNT 4
95% CI 3 to 6 		Small effect size paroxetine (40 mg/day)
[57]
RCT
5-armed trial 		681 people, 274 people in this analysis Mean change in HAM-A total score 12 weeks
with paroxetine (20 mg/day)
with placebo
Absolute numbers not reported
Difference between groups –0.51
95% CI –2.33 to +1.32
P = 0.585 		Not significant
[57]
RCT
5-armed trial 		274 people Mean CGI-Improvement (CGI-I) scores weeks 4, 8, and 10
with paroxetine (20 mg/day)
with placebo
Absolute results reported graphically
P <0.05 		Effect size not calculated paroxetine
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Quality of life

No data from the following reference on this outcome.[51] [63] [57]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[63]
RCT
3-armed trial 		565 people People with at least one adverse event 8 weeks
88% with paroxetine (20 mg/day)
86% with paroxetine (40 mg/day)
74% with placebo
P <0.002 		Effect size not calculated placebo
[57]
RCT
5-armed trial 		681 people Anorgasmia over 12 weeks
9/139 (6.5%) with paroxetine (20 mg/day)
6/136 (4.4%) with escitalopram (10 mg/day)
0/139 (0%) with placebo
P <0.05 		Effect size not calculated placebo
[57]
RCT
5-armed trial 		681 people Insomnia
10% with escitalopram or paroxetine
2% with placebo
Absolute numbers not reported
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No data from the following reference on this outcome.[51]

Sertraline versus placebo:

We found three RCTs.[64] [65] [66]

Symptom severity

Compared with placebo Sertraline seems more effective at 12 weeks at improving Hamilton Anxiety Scale (HAM-A) and Clinical Global Impressions Scale (CGI) scores (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[64]
RCT		 373 people Hamilton Anxiety Scale (HAM-A) score (mean change from baseline) 12 weeks
11.7 with sertraline (dose titrated from 25 mg/day in the first week to 50–150 mg/day by week 12)
–8.0 with placebo
P <0.0001 		Effect size not calculated sertraline
[64]
RCT		 373 people Anxiety component of Hospital Anxiety and Depression (HAD) scale (mean change from baseline) 12 weeks
–4.5 with sertraline (dose titrated from 25 mg/day in the first week to 50–150 mg/day by week 12)
–2.6 with placebo
P <0.0001 		Effect size not calculated sertraline
[64]
RCT		 373 people Clinical Global Impressions Scale (CGI) (mean change from baseline at end point) 12 weeks
1.56 with sertraline (dose titrated from 25 mg/day in the first week to 50–150 mg/day by week 12)
–0.90 with placebo
P <0.0001 		Effect size not calculated sertraline
[65]
RCT		 373 people HAM-A score improvement 12 weeks
with sertraline
with placebo
Absolute numbers not reported
Mean ratio 1.5
95% CI 1.3 to 1.6
Mean difference 3.7
95% CI 3.5 to 3.9 		Effect size not calculated sertraline
[65]
RCT		 373 people CGI score improvement 12 weeks
with sertraline
with placebo
Absolute numbers not reported
Mean ratio 1.33
95% CI 1.27 to 1.3
Mean difference 0.40
95% CI 0.34 to 0.46 		Effect size not calculated sertraline
[65]
RCT		 373 people Response rates (30% reduction in HAM-A) 12 weeks
73% with sertraline
40% with placebo
Absolute numbers not reported
P = 0.001 		Effect size not calculated sertraline
[65]
RCT		 373 people Response rates (50% reduction in HAM-A) 12 weeks
55% with sertraline
32% with placebo
Absolute numbers not reported
P = 0.001 		Effect size not calculated sertraline
[66]
RCT		 326 people Reduction in HAM-A total score from baseline 10 weeks
–12.71 with sertraline (50–200 mg/day)
–11.5 with placebo
P = 0.032 		Effect size not calculated sertraline
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Quality of life

Compared with placebo Sertraline seems more effective at improving quality of life at 12 weeks as assessed by the Quality-of-Life Enjoyment and Satisfaction Questionnaire (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[64]
RCT		 373 people Quality of Life Enjoyment and Satisfaction Questionnaire (mean change from baseline) 12 weeks
9% with sertraline (dose titrated from 25 mg/day in the first week to 50–150 mg/day by week 12)
2% with placebo
Absolute numbers not reported
P <0.0001 		Effect size not calculated sertraline
Open in a new tab

No data from the following reference on this outcome.[65] [66]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[66]
RCT		 328 people Mean change in diastolic blood pressure over 10 weeks
+1.59 mmHg with sertraline
–0.63 mmHg with placebo
P = 0.02 		Effect size not calculated placebo
[66]
RCT		 328 people Mean weight loss over 10 weeks
–1.94 lbs with sertraline
+1.07 lbs with placebo
P = 0.0002 		Effect size not calculated placebo
[66]
RCT		 328 people Proportion of people with decrease in libido over 10 weeks
29/165 (18%) with sertraline
4/163 (2%) with placebo
P <0.01 		Effect size not calculated placebo
[66]
RCT		 Men with anxiety disorder Sexual dysfunction over 10 weeks
with sertraline
with placebo
Significance not assessed
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No data from the following reference on this outcome.[64] [65]

Venlafaxine versus placebo:

We found two systematic reviews (search date 2002, 8 RCTs;[51] and search date 2002, 7 RCTs[30]), one additional RCT,[67] and three subsequent RCTs.[68] [69] [59] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Compared with placebo Venlafaxine may be more effective at increasing response and remission rates (measured as reduction in Hamilton Anxiety Scale [HAM-A] and Clinical Global Impressions Scale [CGI] scores) at 8 to 28 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[70]
RCT
4-armed trial 		365 people
In review [51] 		Response rates (response defined as Clinical Global Impressions Scale [CGI] score of 1 or 2) 8 weeks
54/87 (62%) with venlafaxine (75 mg/day)
38/98 (39%) with placebo
P = 0.002 venlafaxine 75 mg v placebo 		Effect size not calculated venlafaxine (75 mg/day)
[70]
RCT
4-armed trial 		365 people
In review [51] 		Response rates (response defined as CGI score of 1 or 2) 8 weeks
44/87 (49%) with venlafaxine (150 mg/day)
38/98 (39%) with placebo
P value not reported for venlafaxine 150 mg v placebo
[51]
Systematic review		 558 people
2 RCTs in this analysis		 Non-treatment response 8 to 28 weeks
with venlafaxine
with placebo
Absolute numbers not reported
RR 0.68
95% CI 0.46 to 0.99
NNT 5
95% CI 4 to 9 		Small effect size venlafaxine
[30]
Systematic review		 1626 people
5 RCTs in this analysis		 Symptoms
with venlafaxine
with placebo
Absolute results not reported
Reported as improved with venlafaxine
P value not reported
[68]
RCT		 244 people with GAD and depression, recruited from general practice Response rates (50% reduction in Hamilton Anxiety Scale [HAM-A]) 24 weeks
52% with venlafaxine (sustained release 75–150 mg/day)
48% with placebo
Absolute numbers not reported
P = 0.68 		Not significant
[59]
RCT
3-armed trial 		392 people Mean difference in HAM-A 8 weeks
with venlafaxine extended release
with placebo
Absolute numbers not reported
Mean difference –2.27
P = 0.01 		Effect size not calculated venlafaxine
[68]
RCT		 244 people with GAD and depression, recruited from general practice Remission rate (defined as HAM-A score of >7) 24 weeks
28% with venlafaxine (sustained release 75–150 mg/day)
19% with placebo
Absolute numbers not reported
P = 0.11 		Not significant
[68]
RCT		 244 people with GAD and depression, recruited from general practice CGI score of 1 or 2 (meaning "much" or "very" improved) 24 weeks
65% with venlafaxine (sustained release 75–150 mg/day)
46% with placebo
Absolute numbers not reported
P = 0.003 		Effect size not calculated venlafaxine
[67]
RCT		 46 people Remission rates (defined as a score of 7 or less in HAM-A) 8 weeks
15/24 (63%) with venlafaxine (75 mg/day)
2/22 (9%) with placebo
P = 0.0006 		Effect size not calculated venlafaxine
[67]
RCT		 46 people HAM-A (mean change from baseline) 8 weeks
–19.2 with venlafaxine (75 mg/day)
–10.8 with placebo
P <0.001 		Effect size not calculated venlafaxine
[67]
RCT		 42 people CGI-Severity (mean change from baseline) 8 weeks
–2.4 with venlafaxine (75 mg/day)
–1.2 with placebo
P = 0.002 		Effect size not calculated venlafaxine
[67]
RCT		 42 people CGI-Improvement (mean change from baseline) 8 weeks
–1.8 with venlafaxine (75 mg/day)
–0.6 with placebo
P = 0.012 		Effect size not calculated venlafaxine
[67]
RCT		 42 people Covi Anxiety Scale (mean change from baseline) 8 weeks
–4.8 with venlafaxine (75 mg/day)
–3.3 with placebo
P = 0.056 		Not significant
[69]
RCT
4-armed trial 		421 people Mean change in HAM-A 6 weeks
–14.1 with venlafaxine (75 mg/day)
–11.6 with placebo
P = 0.03 		Effect size not calculated venlafaxine
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Quality of life

Compared with placebo Venlafaxine is more effective at 6 months at decreasing the proportion of people with moderately impaired social function (high-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[71]
RCT		 544 people
Further report of reference [51] 		Proportion of people with no/minimal social impairment following treatment 6 months
78/125 (62%) with venlafaxine (37.5 mg/day)
83/115 (72%) with venlafaxine (75 mg/day)
94/118 (80%) with venlafaxine (150 mg/day)
63/111 (56%) with placebo
Significance not assessed
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No data from the following reference on this outcome.[30] [59] [67] [68] [69]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[51]
Systematic review		 People with anxiety disorders Adverse effects
with venlafaxine
with placebo
Significance not assessed
[67]
RCT		 42 people Adverse events
41.7% with venlafaxine
40.9% with placebo
Significance not assessed
[68]
RCT		 244 people with GAD and depression, recruited from general practice Adverse effects
with venlafaxine (sustained release 75–150 mg/day)
with placebo
Absolute numbers not reported
Significance not assessed
[68]
RCT		 244 people with GAD and depression, recruited from general practice Nausea
31% with venlafaxine
10% with placebo
Absolute numbers not reported
P value not reported
[68]
RCT		 244 people with GAD and depression, recruited from general practice Sweating
13% with venlafaxine
2% with placebo
Absolute numbers not reported
P value not reported
[59]
RCT
3-armed trial 		392 people Adverse effects 8 weeks
with venlafaxine extended release
with placebo
Absolute numbers not reported
P <0.05 		Effect size not calculated placebo
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No data from the following reference on this outcome.[69]

Antidepressants versus each other:

We found one systematic review (search date 2002, 8 RCTs),[51] and three subsequent RCTs.[72] [73] [57] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Antidepressants compared with each other We don't know whether one antidepressant is more effective than another at improving response rates (measured as reduction in Hamilton Anxiety Scale [HAM-A] and Clinical Global Impressions Scale [CGI] scores) at 8 weeks (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[74]
RCT		 81 people
In review [51] 		Proportion of people who failed to respond 8 weeks
3/36 (8%) with paroxetine
2/30 (7%) with imipramine
RR of failing to respond 1.73
95% CI 0.31 to 9.57 		Not significant
[73]
RCT		 55 people Rate of response (defined as 50% reduction in Hamilton Anxiety Scale [HAM-A]) 8 weeks
17/25 (68%) with paroxetine
17/28 (61%) with sertraline
RR 1.1
95% CI 0.7 to 1.6 		Not significant
[73]
RCT		 55 people Rate of remission (defined as HAM-A <7) 8 weeks
10/25 (40%) with paroxetine
14/28 (50%) with sertraline
RR 0.8
95% CI 0.4 to 1.4 		Not significant
[73]
RCT		 55 people Clinical Global Impressions Scale [CGI] rating "normal" 8 weeks
10/25 (40%) with paroxetine
13/28 (46%) with sertraline
RR 0.8
95% CI 0.5 to 1.5 		Not significant
[72]
RCT		 121 people Response (defined as CGI of 1 or 2) 24 weeks
with escitalopram
with paroxetine
Absolute numbers not reported
RR 1.25
95% CI 0.99 to 1.59
Results should be interpreted with caution, as there were differences in withdrawal rates between groups, and discontinuation syndrome 		Not significant
[72]
RCT		 121 people HAM-A scale 24 weeks
with escitalopram
with paroxetine
Absolute numbers not reported
Mean difference: 2.0
95% CI 0.63 to 4.63
Results should be interpreted with caution as there were differences in withdrawal rates between groups, and discontinuation syndrome 		Effect size not calculated paroxetine
[72]
RCT		 121 people CGI scale 24 weeks
with escitalopram
with paroxetine
Absolute numbers not reported
Mean difference: +0.3
95% CI –0.77 to +1.37
Results should be interpreted with caution as there were differences in withdrawal rates between groups, and discontinuation syndrome 		Not significant
[57]
RCT
5-armed trial 		270 people Mean change in HAM-A scores 12 weeks
with escitalopram (10 mg/day)
with paroxetine (20 mg/day)
Absolute numbers not reported
Mean difference: –2.06
95% CI –3.90 to –0.21 		Effect size not calculated escitalopram (10 mg/day)
[57]
RCT
5-armed trial 		270 people Response (defined as at least a 50% decrease in HAM-A score) 12 weeks
72% with escitalopram (10 mg/day)
60% with paroxetine (20 mg/day)
Absolute numbers not reported
P <0.05 		Effect size not calculated escitalopram (10 mg/day)
[57]
RCT
5-armed trial 		270 people Remission (defined as HAM-A score <7) 12 weeks
48% with escitalopram (10 mg/day)
33% with paroxetine (20 mg/day)
Absolute numbers not reported
P <0.05 		Effect size not calculated escitalopram (10 mg/day)
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Quality of life

No data from the following reference on this outcome.[57] [72] [73] [74]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[72]
RCT		 121 people Overall adverse effects
77% with escitalopram
89% with paroxetine
Absolute numbers not reported
[72]
RCT		 121 men and women Ejaculation disorder
30% of men with escitalopram
14% of men with paroxetine
Absolute numbers not reported
Reported as significant
P value not reported 		Effect size not calculated paroxetine
[72]
RCT		 121 men and women Decreased libido
26% with escitalopram
5% with paroxetine
Absolute numbers not reported
Reported as significant
P value not reported 		Effect size not calculated paroxetine
[72]
RCT		 121 men and women Anorgasmia
26% with escitalopram
7% with paroxetine
Absolute numbers not reported
Reported as significant
P value not reported 		Effect size not calculated paroxetine
[57]
RCT
5-armed trial 		681 people Anorgasmia over 12 weeks
6/136 (5%) with escitalopram (10 mg/day)
9/139 (7%) with paroxetine (20 mg/day)
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No data from the following reference on this outcome.[73] [74]

Antidepressants versus benzodiazepines:

We found two reviews (search dates 2002)[51] [30] and one subsequent RCT.[75] The first review[51] included two RCTs,[53] [74] and the second review[30] included one RCT.[62] The first RCT[53] identified by the first review[51] found similar improvements with imipramine, trazodone, diazepam, and placebo, but did not directly compare the significance of differences between groups. See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Antidepressants compared with benzodiazepines Antidepressants and benzodiazepines seem equally effective at 8 weeks at improving anxiety (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[74]
RCT
3-armed trial 		81 people
In review [51] 		Anxiety (mean Hamilton Anxiety Scale [HAM-A] score) 8 weeks
10.8 with imipramine
12.9 with 2'-chlordesmethyldiazepam
P = 0.05 		Not significant
[74]
RCT
3-armed trial 		81 people
In review [51] 		Anxiety (mean HAM-A score) 8 weeks
11.1 with paroxetine
12.9 with 2'-chlordesmethyldiazepam
P = 0.05 		Not significant
[62]
RCT
3-armed trial 		318 people
In review [30] 		Response (defined as Clinical Global Impressions Scale [CGI] of <2) 28 days
63% with opipramol
64% with alprazolam
Absolute numbers not reported
[75]
RCT		 80 people HAM-A improvement 6 weeks
13.7 with paroxetine
10.8 with lorazepam
P >0.05 		Not significant
[75]
RCT		 80 people Self-rating Anxiety Scale (SAS)
16.5 with paroxetine
14.4 with lorazepam
P >0.05 		Not significant
[75]
RCT		 80 people Recovery 6 weeks
18/40 (45%) with paroxetine
16/40 (40%) with lorazepam
P >0.05 		Not significant
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Quality of life

No data from the following reference on this outcome.[53] [62] [74] [75]

Adverse effects

No data from the following reference on this outcome.[53] [62] [74] [75]

Antidepressants versus buspirone:

We found one systematic review (search date 2002, 8 RCTs),[51] which identified one RCT.[70] See also comment section for further information from observational studies and comments on adverse effects of antidepressants.

Symptom severity

Antidepressants compared with buspirone The antidepressant venlafaxine and buspirone seem equally effective at improving response rates at 8 weeks (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[70]
RCT
3-armed trial 		365 people
In review [51] 		Rates of response (defined as Clinical Global Impressions Scale [CGI] of 1 or 2) 8 weeks
54/87 (62%) with venlafaxine (75 mg)
44/89 (49%) with venlafaxine (150 mg)
52/95 (55%) with buspirone
Significance not assessed
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Quality of life

No data from the following reference on this outcome.[70]

Adverse effects

No data from the following reference on this outcome.[70]

Further information on studies

The RCT compared continued escitalopram 20 mg daily over 24 to 76 weeks versus placebo in 375 people. 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 continued escitalopram or placebo.

A re-analysis of the same trials found a pooled effect size of 0.3 compared with placebo.

Comment

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

We found one systematic review that used a Bayesian approach to perform a mixed-treatment meta-analysis of 9 medications including 6 antidepressants (duloxetine, escitalopram, fluoxetine, paroxetine, sertraline, venlafaxine).[77] A probabilistic analysis was used to rank the treatments. The order of ranking differed by outcome: for response, the rank order of antidepressants was: fluoxetine, duloxetine, sertraline, paroxetine, venlafaxine, and escitalopram. For remission (final Hamilton Anxiety Scale [HAM-A] score 7 or less), the rank order was: fluoxetine, escitalopram, venlafaxine, paroxetine, sertraline, and duloxetine. The rank order for withdrawing from the trial owing to adverse effects (most withdrawals first) was: sertraline, fluoxetine, paroxetine, venlafaxine, escitalopram, and duloxetine.[77]

Nausea:

There have been case reports of nausea in people taking paroxetine.[74]

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 <0.01 for paroxetine or sertraline v fluoxetine).[78] 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 <0.001).[57]

Overdose:

In a series of 239 coroner-directed necropsies from 1970 to 1989, tricyclic antidepressants (TCAs) were considered a causal factor in 12% of deaths, and hypnosedatives (primarily benzodiazepines and excluding barbiturates) in 8%.[79]

Accidental poisoning:

TCAs are a major cause of accidental poisoning.[80] A study estimated that there was one death for every 44 children admitted to hospital after ingestion of TCAs.[81]

Hyponatraemia:

One case series reported 736 incidents of hyponatraemia in people taking SSRIs; 83% of episodes were in hospital inpatients aged >65 years.[82] 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).[83] 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).[84] 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.[85] The FDA 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 MHRA.[86]

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.[87]

Suicide:

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

Substantive changes

Antidepressants in adults New evidence added.[52] [54] [55] [59] [60] [69] Categorisation changed from Likely to be beneficial to Beneficial.

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Antipsychotics in adults

Summary

Antipsychotic drugs may reduce anxiety in people who have not responded to other treatments, but these drugs may have adverse effects including drowsiness and movement disorders.

Benefits and harms

Antipsychotics versus placebo:

We found two systematic reviews (search dates 2005[88] and 2010[89]). The first review included three RCTs of older antipsychotics.[88] It did not pool data. Of the included RCTs, two were in people with generalised anxiety disorder (GAD). (See Clinical Evidence review on schizophrenia for additional information about adverse effects of antipsychotics.)

Symptom severity

Compared with placebo Antipsychotics (trifluoperazine, chlorprothixene, and quetiapine) may be more effective at improving Hamilton Anxiety Scale (HAM-A) scores, and quetiapine may be more effective at reducing relapse and at increasing response over the longer term; but antipsychotics also cause more adverse effects (such as drowsiness, extrapyramidal reactions, weight gain, and movement disorders) compared with placebo (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[88]
Systematic review		 413 people
Data from 1 RCT		 Hamilton Anxiety Scale (HAM-A) score
with trifluoperazine (2–6 mg/day)
with placebo
Absolute results not reported
P <0.001 		Effect size not calculated trifluoperazine
[88]
Systematic review		 31 people
Data from 1 RCT		 "Outcomes" (not further specified)
with flupentixol
with placebo
Absolute results not reported
Reported as not significant
P value not reported 		Not significant
[88]
Systematic review		 139 people
Data from 1 RCT		 Median reductions in HAM-A scores 2 weeks
10.3 with chlorprothixene
7.3 with placebo
Statistical analysis between groups not reported
The RCT was short (2 weeks), which may not have allowed differences in outcomes to become apparent
[89]
Systematic review		 2262 people
4 RCTs in this analysis		 Proportion of people responding to treatment
811/1369 (59%) with quetiapine
379/893 (42%) with placebo
RR 2.21
95% CI 1.10 to 4.45
P = 0.026 		Moderate effect size quetiapine
[89]
Systematic review		 433 people
Data from 1 RCT		 Proportion of people relapsing after responding to treatment
22/216 (10%) with quetiapine
85/217 (39%) with placebo
RR 0.18
95% CI 0.10 to 0.30
P <0.00001 		Large effect size quetiapine
[89]
Systematic review		 2256 people
4 RCTs in this analysis		 Mean change in HAM-A (short-term trials)
with quetiapine
with placebo
Absolute numbers not reported
Mean difference –2.58
95% CI –4.00 to –1.16
P <0.0004 		Effect size not calculated quetiapine
[89]
Systematic review		 432 people
Data from 1 RCT		 Mean change in HAM-A (long-term trials)
with quetiapine
with placebo
Absolute numbers not reported
Mean difference –2.04
95% CI –3.25 to –0.83
P <0.001 		Effect size not calculated quetiapine
[89]
Systematic review		 2256 people
4 RCTs in this analysis		 Proportion of people with a clinically significant change in Clinical Global Impressions Scale [CGI]
869/1369 (63%) with quetiapine
412/893 (46%) with placebo
OR 2.28
95% CI 1.01 to 5.14
P = 0.046 		Moderate effect size quetiapine
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Quality of life

No data from the following reference on this outcome.[88] [89]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[90]
RCT		 413 people
In review [88] 		Drowsiness
43% with trifluoperazine
25% with placebo
Absolute numbers not reported
Significance not assessed
[90]
RCT		 413 people
In review [88]
11 RCTs in this analysis		 Extrapyramidal reactions and movement disorders
17% with trifluoperazine
8% with placebo
Absolute numbers not reported
Significance not assessed
[89]
Systematic review		 450 people
Data from 1 RCT		 Proportion of people with at least 1 adverse effect
145/223 (65%) with quetiapine
114/227 (50%) with placebo
OR 1.84
95% CI 1.26 to 2.69
P <0.002 		Small effect size placebo
[89]
Systematic review		 2262 people
4 RCTs in this analysis		 Proportion of people with extrapyramidal adverse effects
63/1369 (5%) with quetiapine
25/893 (3%) with placebo
OR 1.80
95% CI 1.12 to 2.90
P <0.016 		Small effect size placebo
[89]
Systematic review		 2201 people
4 RCTs in this analysis		 Mean change in weight (kg)
with quetiapine
with placebo
Absolute numbers not reported
Mean difference 0.63 kg
95% CI 0.40 kg to 0.86 kg
P <0.00001 		Effect size not calculated placebo
[89]
Systematic review		 437 people
Data from 1 RCT		 Increase in prolactin (ng/mL)
with quetiapine
with placebo
Absolute numbers not reported
Mean difference +0.70 ng/mL
95% CI –1.09 ng/mL to +2.49 ng/mL
P = 0.44 		Not significant
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Further information on studies

None.

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 New evidence added.[89] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Pregabalin in adults

Summary

Pregabalin may reduce symptoms of anxiety in people with GAD, but can have unpleasant adverse effects, and most trials have been short term.

Benefits and harms

Pregabalin versus placebo:

We found one narrative systematic review (search date 2006),[91] which did not perform a meta-analysis. The review identified 4 RCTs, including 2 RCTs already reported in detail here.[92] [93] As the review[91] did not perform a meta-analysis, we continue to report those individual RCTs here.[92] [93]We found two subsequent RCTs.[69] [94]

Symptom severity

Compared with placebo Pregabalin may be more effective at 4 weeks at improving Hamilton Anxiety Scale (HAM-A) and Clinical Global Impressions Scale (CGI) scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[91]
Systematic review
4-armed trial 		276 people
Data from 1 RCT		 Reduction in Hamilton Anxiety Scale (HAM-A) scores 4 weeks
with pregabalin (150 mg/day)
with placebo
Absolute numbers not reported
P value not reported
Reported as not significant 		Not significant
[91]
Systematic review
4-armed trial 		276 people
Data from 1 RCT		 Reduction in HAM-A scores 4 weeks
with pregabalin (600 mg/day)
with placebo
Absolute numbers not reported
P <0.01
No further data reported 		Effect size not calculated pregabalin (600 mg/day)
[91]
Systematic review
4-armed trial 		341 people
Data from 1 RCT		 Reduction in HAM-A scores 4 weeks
with pregabalin (200 mg/day)
with placebo
Absolute numbers not reported
P = 0.006
No further data reported 		Effect size not calculated pregabalin (200 mg/day)
[91]
Systematic review
4-armed trial 		341 people
Data from 1 RCT		 Reduction in HAM-A scores 4 weeks
with pregabalin (400 mg/day)
with placebo
Absolute numbers not reported
P = 0.001
No further data reported 		Effect size not calculated pregabalin (400 mg/day)
[91]
Systematic review
4-armed trial 		341 people
Data from 1 RCT		 Reduction in HAM-A scores 4 weeks
with pregabalin (450 mg/day)
with placebo
Absolute results not reported
P = 0.005
No further data reported 		Effect size not calculated pregabalin (450 mg/day)
[92]
RCT
4-armed trial 		271 people
In review [91] 		HAM-A total scores 4 weeks
with pregabalin (50 mg/day)
with placebo
Absolute results not reported
Mean difference –1.62 (pregabalin 50 mg v placebo)
95% CI –3.90 to +0.67
P >0.16 		Not significant
[92]
RCT
4-armed trial 		271 people
In review [91] 		HAM-A total scores 4 weeks
with pregabalin (200 mg/day)
with placebo
Absolute results not reported
Mean difference –3.90 (pregabalin 200 mg v placebo)
95% CI –6.26 to –1.54
P = 0.0013 		Effect size not calculated pregabalin (200 mg/day)
[92]
RCT
4-armed trial 		271 people
In review [91] 		Rates of response
36/62 (59%) with pregabalin (200 mg/day)
36/69 (52%) with pregabalin (50 mg/day)
29/66 (44%) with placebo
P >0.34 (pregabalin 50 mg/day v placebo)
P >0.09 (pregabalin 200 mg/day v placebo) 		Not significant
[93]
RCT
5-armed trial 		454 people, randomised in blocks of 10
In review [91] 		HAM-A scores from baseline at 4 weeks
with pregabalin (300 mg/day)
with placebo
Absolute results not reported
Mean difference from placebo in reduction in HAM-A score −3.89
95% CI −6.05 to −1.73
P <0.001 		Effect size not calculated pregabalin (300 mg/day)
[93]
RCT
5-armed trial 		454 people, randomised in blocks of 10
In review [91] 		HAM-A scores from baseline at 4 weeks
with pregabalin (450 mg/day)
with placebo
Absolute results not reported
Mean difference from placebo in reduction in HAM-A score −2.65
95% CI −4.82 to −0.48
P = 0.2 		Not significant
[93]
RCT
5-armed trial 		454 people, randomised in blocks of 10
In review [91] 		HAM-A scores from baseline at 4 weeks
with pregabalin (600 mg/day)
with placebo
Absolute results not reported
Mean difference from placebo in reduction in HAM-A score −3.43
95% CI −5.62 to −1.25
P = 0.02 		Effect size not calculated pregabalin (600 mg/day)
[69]
RCT
4-armed trial 		421 people Mean change in HAM-A 6 weeks
–14.7 with pregabalin (400 mg/day)
–11.6 with placebo
P = 0.008 		Effect size not calculated pregabalin (400 mg/day)
[69]
RCT
4-armed trial 		421 people Mean change in HAM-A 6 weeks
–14.1 with pregabalin (600 mg/day)
–11.6 with placebo
P = 0.03 		Effect size not calculated pregabalin (600 mg/day)
[94]
RCT		 273 older people (mean age 72 years) Mean change from baseline in HAM-A 8 weeks
–15.4 with pregabalin (150–600 mg/day)
–12.7 with placebo
P = 0.096 		Not significant
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Quality of life

No data from the following reference on this outcome.[92] [93] [91] [69] [94]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[92]
RCT
4-armed trial 		271 people
In review [91] 		Proportion of people with adverse events
59 (89%) with pregabalin (200 mg/day)
51 (73%) with pregabalin (50 mg/day)
45 (67%) with placebo
Open in a new tab

No data from the following reference on this outcome.[93] [69] [94]

Pregabalin versus benzodiazepines:

We found two RCTs.[92] [93]

Symptom severity

Compared with benzodiazepines We don't know whether pregabalin is more effective than benzodiazepines at 4 weeks at improving Hamilton Anxiety Scale (HAM-A) or Clinical Global Impressions Scale (CGI) scores (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[92]
RCT
4-armed trial 		271 people
In review [91] 		Hamilton Anxiety Scale (HAM-A) total scores 4 weeks
with pregabalin (200 mg/day)
with lorazepam (2 mg/day)
Absolute results not reported
P >0.1 for lorazepam (2 mg/day) v pregabalin (200 mg/day) 		Not significant
[92]
RCT
4-armed trial 		271 people
In review [91] 		HAM-A total scores 4 weeks
with pregabalin (50 mg/day)
with lorazepam (2 mg/day)
Absolute results not reported
P >0.5 for lorazepam (2 mg/day) v pregabalin (50 mg/day) 		Not significant
[93]
RCT
5-armed trial 		454 people, randomised in blocks of 10
In review [91] 		Response rates (at least 50% improvement in HAM-A score or Clinical Global Impressions Scale (CGI) rating of "very much improved" or "much improved") 4 weeks
61% with pregabalin (300 mg/day)
43% with alprazolam (1.5 mg/day)
Absolute results reported graphically
P <0.05 		Effect size not calculated pregabalin (300 mg/day)
Open in a new tab

Quality of life

No data from the following reference on this outcome.[92] [93]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[92]
RCT
4-armed trial 		271 people
In review [91] 		Proportion of people with adverse events
59/66 (89%) with pregabalin (200 mg/day)
51/70 (73%) with pregabalin (50 mg/day)
62/68 (91%) with lorazepam (2 mg/day)
Open in a new tab

No data from the following reference on this outcome.[93]

Further information on studies

None.

Comment

None.

Substantive changes

Pregabalin in adults New evidence added.[69] [91] [94]

BMJ Clin Evid. 2011 Oct 27;2011:1002.

CBT in children and adolescents

Summary

CBT improves symptoms compared with waiting list control or active control. Most RCTs of CBT in children and adolescents have included other anxiety disorders. We found no trials in participants with GAD alone.

Benefits and harms

CBT versus waiting list control or active control:

We found 4 systematic reviews (search dates 2003,[95] 2002,[96] 2004,[97] and 2008[98]). In the systematic reviews, no included RCT examined the effects of CBT in children or adolescents with generalised anxiety disorder (GAD) alone (see further information on studies and comment, below). None of the reviews performed a meta-analysis. We found two RCTs[99] [100] included in the first three reviews that satisfied Clinical Evidence inclusion criteria and two RCTs[101] [102] in the most recent review. We found 8 subsequent RCTs.[103] [104] [105] [106] [107] [108] [109] [110]

Symptom severity

Compared with waiting list control or active control CBT may be more effective at improving remission rates and at reducing symptoms in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[97]
Systematic review		 45 participants aged 8 to 14 years, 21 (47%) with GAD, 11 (24%) with separation anxiety disorder (SAD), 5 (11%) with social anxiety disorder (SOP)
Data from 1 RCT		 Proportion of people with anxiety diagnosis
17/31 (55%) with CBT (individual or group)
14/14 (100%) with waiting list control
RR 0.55
95% CI 0.40 to 0.75 		Small effect size CBT
[97]
Systematic review		 71 people aged 7 to 14 years, 42 (59%) with GAD, 19 (27%) with SAD, 10 (14%) with SOP
Data from 1 RCT		 Proportion of people with anxiety diagnosis
21/54 (39%) with group-based CBT
15/17 (88%) with waiting list control
RR 0.44
95% CI 0.30 to 0.64 		Moderate effect size CBT
[103]
RCT
3-armed trial 		61 children aged 7 to 11 years, 20 (33%) with primary diagnosis of GAD, 17 (28%) with GAD in conjunction with other anxiety disorder Improvement in clinician severity rating score
with group CBT
with group CBT plus parent training
with no treatment
Absolute numbers not reported
P = 0.03 for both CBT groups combined v no treatment group
Some additional benefit was noted with the use of parent training 		Effect size not calculated CBT
[104]
RCT
4-armed trial 		100 children aged 6 to 12 years, 40% with GAD as the principal diagnosis, 32% with GAD in conjunction with another anxiety disorder Percentage of children no longer meeting criteria for anxiety disorder
79% with therapist-initiated telephone support plus CBT
33% with therapist-initiated email support plus CBT
31% with client-initiated support plus CBT
1% with waiting list control
Absolute numbers not reported
P <0.01 (all active treatments v waiting list control)
P <0.01 (any individual active treatment v waiting list control) 		Effect size not calculated support plus CBT
[105]
RCT
3-armed trial 		267 children aged 6 to 12 years, 103 (39%) with GAD Percentage of children free from anxiety disorder after treatment
49% with group CBT
18% with parent bibliotherapy (including self-help anxiety-management books, workbooks, and worksheets used by the CBT group)
6% with waiting list control
Absolute numbers not reported
P <0.05 (bibliotherapy v waiting list control)
P <0.001 (bibliotherapy v group CBT) 		Effect size not calculated group CBT
[107]
RCT
4-armed trial 		488 children aged 7 to 17 years with anxiety disorders; 79% had GAD Response (proportion of children much improved or better) 12 weeks
60% with CBT
24% with placebo
Absolute numbers not reported
OR 4.8
95% CI 2.6 to 9.0
P <0.001 		Moderate effect size CBT
[108]
RCT		 112 children aged 7 to 16 years with anxiety disorders; 53% had GAD Proportion of children who did not meet diagnostic criteria for their principal anxiety diagnosis after 3 months' treatment
23/51 (45%) with CBT
13/44 (30%) with group support and attention
P <0.1 		Not significant
[108]
RCT		 112 children aged 7 to 16 years with anxiety disorders; 53% had GAD Proportion of children who did not meet diagnostic criteria for their principal anxiety diagnosis 6 months post treatment
35/51 (69%) with CBT
20/44 (45%) with group support and attention
P <0.05 		Effect size not calculated CBT
[109]
RCT		 64 children aged 4 to 7 years with anxiety disorders; 38% had GAD Response (proportion of children much improved or better) post treatment
20/34 (59%) with CBT
9/30 (30%) with waiting list control
P = 0.016 		Effect size not calculated CBT
[110]
RCT		 45 children aged 6 to 11 years; 38% had GAD Proportion of children who did not meet criteria for an anxiety disorder 13 weeks
13/20 (65%) with CBT
0/21 (0%) with waiting list control
P <0.01 		Effect size not calculated CBT
[101]
RCT
3-armed trial 		72 children aged 7 to 14 years with an anxiety disorder; 28% had GAD
In review [98] 		Proportion of children free of anxiety disorder diagnosis 10 weeks
11/20 (55%) with clinic-based group CBT
2/23 (7%) with waiting list control
P = 0.002 		Effect size not calculated clinic-based group CBT
[101]
RCT
3-armed trial 		72 children aged 7 to 14 years with an anxiety disorder; 28% had GAD
In review [98] 		Proportion of children free of anxiety disorder diagnosis 10 weeks
11/25 (45%) with group CBT partially delivered via the internet (CLIN-NET)
2/23 (7%) with waiting list control
P = 0.006 		Effect size not calculated CLIN-NET
[101]
RCT
3-armed trial 		72 children aged 7 to 14 years with an anxiety disorder; 28% had GAD
In review [98] 		Mean change in Children's Depression Inventory 10 weeks
From 48.45 to 42.50 with clinic-based group CBT
From 53.48 to 50.00 with waiting list control
P value not reported
Reported as not significant 		Not significant
[101]
RCT
3-armed trial 		72 children aged 7 to 14 years with an anxiety disorder; 28% had GAD
In review [98] 		Mean change in Children's Depression Inventory (CDI) 10 weeks
From 55.07 to 46.96 with group CBT partially delivered via the internet (CLIN-NET)
From 53.48 to 50.00 with waiting list control
P = 0.017 		Effect size not calculated CLIN-NET
[102]
RCT		 73 children aged 7 to 12 years with anxiety disorders; 23% had primary diagnosis of GAD
In review [98] 		Mean change in Children's Global Assessment Scale 10 weeks
From 50.87 to 61.73 with internet-based CBT
From 51.72 to 54.93 with waiting list control
P = 0.065 		Not significant
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No data from the following reference on this outcome.[106]

Quality of life

No data from the following reference on this outcome.[97] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110]

Adverse effects

No data from the following reference on this outcome.[97] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110]

Individual versus family or group CBT:

We found no systematic review. We found two RCTs comparing individual versus family CBT[106] [111] and one RCT comparing individual versus group CBT.[112]

Symptom severity

Individual compared with family or group CBT Individual, family, and group CBT may be equally effective at improving symptoms and increasing remission in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[106]
RCT
3-armed trial 		161 children aged 7 to 14 years with anxiety disorders; 55% had GAD Proportion of children for whom the principal diagnosis is no longer the main reason for treatment 12 months
67% with individual CBT (ICBT)
64% with family CBT (FCBT)
Absolute numbers not reported
P value not reported
Reported as not significant 		Not significant
[111]
RCT		 119 children aged 7 to 16 years with anxiety disorders; 42% had GAD; 20% had GAD as primary diagnosis Proportion of children who no longer had primary diagnosis post treatment
78% with CBT
78% with CBT with active parental involvement (CBT/P)
Absolute numbers not reported
P value not reported
Reported as not significant 		Not significant
[112]
RCT		 127 children aged 8 to 12 years with anxiety disorders; 29% had GAD Mean change in Multidimensional Anxiety Scale for Children (MASC) 11 weeks
From 50.85 to 36.94 with ICBT
From 51.43 to 37.00 with group CBT (GCBT)
P value not reported
Reported as not significant 		Not significant
[112]
RCT		 127 children aged 8 to 12 years with anxiety disorders; 29% had GAD Mean change in Children's Depression Inventory (CDI) 11 weeks
From 10.28 to 5.65 with ICBT
From 8.73 to 4.68 with group CBT (GCBT)
P value not reported
Reported as not significant 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[106] [111] [112]

Adverse effects

No data from the following reference on this outcome.[106] [111] [112]

CBT versus drug treatments:

See option on antidepressants in children and adolescents.

Further information on studies

The systematic review pooled data for all included RCTs (age range 7–16 years) including participants with GAD, SAD, SOP, and overanxious disorder. It found that CBT significantly increased remission rate compared with control (10 RCTs; remission rate: 57% with CBT v 35% with control; OR 3.27, 95% CI 1.9 to 5.6).

The third review pooled data on included RCTs (age range 7–17 years) including participants with SAD, SOP, overanxious disorder, GAD, any DSM-IV diagnosis, and avoidant disorder. It found similar results to the first review, in that CBT significantly improved response compared with control (12 RCTs, 765 people; response rate for remission: 56% with CBT v 28% with control; RR 0.58, 95% CI 0.50 to 0.67).

Comment

No included RCT examined the effects of CBT in children or adolescents with generalised anxiety disorder (GAD) alone. Two systematic reviews noted that, while reviews in adults were able to examine the role of CBT separately with regard to GAD or other specific anxiety disorders, the majority of trials in children and adolescents had treated anxiety disorders (e.g., social anxiety disorder [SOP], GAD, separation anxiety disorder [SAD]) as a group together.

It is noted that studies assessing the effects of anxiety treatments on younger children (e.g.,[109]) are much needed if we are to understand the most effective interventions for this group and early intervention and prevention efforts are to be maximised. However, it is also acknowledged that differential diagnosis of GAD versus other anxiety disorders is difficult in very young participants; therefore, the use of participants with mixed anxiety disorders is warranted.

Substantive changes

CBT in children and adolescents New evidence added.[98] [101] [102] [106] [107] [108] [109] [110] [111] [112]Categorisation unchanged (Beneficial).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Applied relaxation in children and adolescents

Summary

We found no RCT evidence on the effects of applied relaxation in children and adolescents.

Benefits and harms

Applied relaxation in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Benzodiazepines in children and adolescents

Summary

We found no RCT evidence on the effects of benzodiazepines in children and adolescents.

Benefits and harms

Benzodiazepines in children and adolescents:

We found no systematic review or RCTs on the effects of benzodiazepines in children or adolescents with generalised anxiety disorder (GAD). We found one small RCT (mean age 12 years; 30 participants with DSM-III overanxious disorder [OAD]).[113] The diagnosis of overanxious disorder (OAD, DSM-III) predates the current classification of GAD (DSM-IV). See comment for further information on this study.

Further information on studies

None.

Comment

The RCT published in 1992 found no significant difference in clinical efficacy measured by clinical global ratings between alprazolam and placebo at 4 weeks (reported as not significant, P value not reported).[113] The study may have been underpowered to detect differences between groups. The RCT reported that adverse effects were mild, and were reported equally by the alprazolam and placebo groups (absolute numbers not reported).

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Buspirone in children and adolescents

Summary

We found no RCT evidence on the effects of buspirone in children and adolescents.

Benefits and harms

Buspirone in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Hydroxyzine in children and adolescents

Summary

We found no RCT evidence on the effects of hydroxyzine in children and adolescents.

Benefits and harms

Hydroxyzine in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Abecarnil in children and adolescents

Summary

We found no RCT evidence on the effects of abecarnil in children and adolescents.

Benefits and harms

Abecarnil in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Antidepressants in children and adolescents

Summary

We found limited RCT evidence regarding the efficacy of antidepressants for childhood GAD. SSRIs (fluvoxamine, fluoxetine, sertraline) have shown some promise, but antidepressants are associated with abdominal pain and nausea, and other well documented adverse effects. The general use of antidepressants in children and adolescents has been the subject of adverse events warnings regarding self-harm and other potential serious adverse effects.

Benefits and harms

Antidepressants versus placebo:

We found one systematic review (search date 2008, 9 RCTs).[114] See comment section for additional information on general harms of antidepressants in children and adolescents.

Symptom severity

Compared with placebo Antidepressants (sertraline, fluoxetine, fluvoxamine, paroxetine, venlafaxine) may be more effective at increasing response and reducing anxiety at up to 16 weeks in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[114]
Systematic review		 1448 children with anxiety disorders including GAD
9 RCTs in this analysis		 Response rate up to 16 weeks
478/748 (64%) with antidepressants (sertraline, fluoxetine, fluvoxamine, paroxetine, venlafaxine)
237/700 (34%) with placebo
RR 2.01
95% CI 1.59 to 2.55
P <0.00001 		Moderate effect size antidepressants
[114]
Systematic review		 428 children with anxiety disorders including GAD
4 RCTs in this analysis		 Change in anxiety scores up to 16 weeks
with antidepressants (sertraline, fluoxetine, fluvoxamine, paroxetine, venlafaxine)
with placebo
Absolute numbers not reported
SMD –0.82
95% CI –1.30 to –0.33
P <0.0001 		Moderate effect size antidepressants
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Quality of life

Antidepressants compared with placebo Sertraline and fluoxetine may be more effective at improving quality-of-life measures at up to 16 weeks in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Quality of life
[114]
Systematic review		 390 children with anxiety disorders including GAD
4 RCTs in this analysis		 Response rate up to 16 weeks
with antidepressants (sertraline, fluoxetine)
with placebo
Absolute numbers not reported
SMD 0.55
95% CI 0.34 to 0.76
P <0.00001 		Moderate effect size antidepressants
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Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[114]
Systematic review		 95 children with anxiety disorders including GAD
2 RCTs in this analysis		 Adverse effects
with antidepressants (sertraline, fluoxetine)
with placebo
Absolute numbers not reported
Significance not assessed
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Fluoxetine versus placebo:

We found one systematic review (search date 2008),[114] which identified one RCT.[115]

Symptom severity

Compared with placebo Fluoxetine may be more effective at improving symptoms of anxiety (as measured by Hamilton Anxiety Scale [HAM-A] and Clinical Global Impressions Scale [CGI] scores) in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[115]
RCT		 74 children and adolescents aged 7 to 17 years with GAD, separation anxiety disorder, and/or social phobia (47/74 [64%] had GAD either with or without another disorder)
In review [114] 		Proportion of people who were much or very much improved (defined as Clinical Global Impression-Improvement [CGI-I] score 2 or less)
22/36 (61%) with fluoxetine
13/37 (35%) with placebo
P = 0.03 		Effect size not calculated fluoxetine
[115]
RCT		 46 children and adolescents aged 7 to 17 years with GAD, either with or without another disorder
In review [114] 		Proportion of people with CGI-I score 2 or less
61% with fluoxetine (20 mg/day)
36% with placebo
Absolute results not reported
P = 0.04 		Effect size not calculated fluoxetine
Open in a new tab

Quality of life

No data from the following reference on this outcome.[115]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[115]
RCT		 74 children and adolescents aged 7 to 17 years with GAD, separation anxiety disorder, and/or social phobia (47/74 [64%] had GAD either with or without another disorder)
In review [114] 		Gastrointestinal adverse effects (abdominal pain and nausea) 2 weeks
16/35 (46%) with fluoxetine
7/37 (19%) with placebo
P = 0.04 		Effect size not calculated placebo
[115]
RCT		 74 children and adolescents aged 7 to 17 years with GAD, separation anxiety disorder, and/or social phobia (47/74 [64%] had GAD either with or without another disorder)
In review [114] 		Withdrawal from trial
with fluoxetine
with placebo
[115]
RCT		 74 children and adolescents aged 7 to 17 years with GAD, separation anxiety disorder, and/or social phobia (47/74 [64%] had GAD either with or without another disorder)
In review [114] 		Neurological complaints (drowsiness and headaches) 2 weeks
16/36 (44%) with fluoxetine
5/36 (14%) with placebo
P = 0.004 		Effect size not calculated placebo
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Fluvoxamine versus placebo:

We found one RCT.[116]

Symptom severity

Compared with placebo Fluvoxamine may be more effective at improving symptoms of anxiety (as measured by Hamilton Anxiety Scale [HAM-A] and Clinical Global Impressions Scale [CGI] scores) in children and adolescents with generalised and other anxiety disorders (low-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[116]
RCT		 128 people aged 6 to 17 years, who previously received 3 weeks of psychological treatment without benefit (73/128 [57%] had GAD with or without another disorder) Mean decrease in Pediatric Anxiety Rating Scale
9.7 with fluvoxamine (300 mg/day, maximum)
3.1 with placebo
P <0.001 		Effect size not calculated fluvoxamine
[116]
RCT		 128 people aged 6 to 17 years, who previously received 3 weeks of psychological treatment without benefit (73/128 [57%] had GAD with or without another disorder) Clinical Global Impression-Improvement [CGI-I] scale, response defined as score <4
48/63 (76%) with fluvoxamine (300 mg/day, maximum)
19/65 (29%) with placebo
P <0.001 		Effect size not calculated fluvoxamine
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Quality of life

No data from the following reference on this outcome.[116]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[116]
RCT		 128 people aged 6 to 17 years, who previously received 3 weeks of psychological treatment without benefit (73/128 [57%] had GAD with or without another disorder) Abdominal discomfort
49% with fluvoxamine
28% with placebo
Absolute numbers not reported
P = 0.02 		Effect size not calculated placebo
[116]
RCT		 128 people aged 6 to 17 years, who previously received 3 weeks of psychological treatment without benefit (73/128 [57%] had GAD with or without another disorder) Increased motor activity
27% with fluvoxamine
8% with placebo
Absolute numbers not reported
P = 0.06 		Not significant
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Sertraline versus placebo:

We found two systematic reviews (search dates 2002[51] and 2008[114]). Both reviews identified the same small RCT.[117] The second review[114] identified one further RCT.[107]

Symptom severity

Compared with placebo Sertraline seems more effective at improving symptoms of anxiety (as measured by Hamilton Anxiety Scale [HAM-A] and Clinical Global Impressions Scale [CGI] scores) and response in children and adolescents with generalised and other anxiety disorders (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[117]
RCT		 22 children and adolescents aged 5 to 17 years with childhood GAD
In review [51] [114] 		Mean Hamilton Anxiety Scale (HAM-A) total score week 9
7.8 with sertraline (50 mg/day maximum)
2.1 with placebo
P <0.001 		Effect size not calculated sertraline
[117]
RCT		 22 children and adolescents aged 5 to 17 years with childhood GAD
In review [51] [114] 		Mean Clinical Global Impressions Scale [CGI] total score week 9
2.4 with sertraline (50 mg/day maximum)
3.9 with placebo
P <0.001 		Effect size not calculated sertraline
[107]
RCT
4-armed trial 		488 children aged 7 to 17 years with GAD or other anxiety disorders
In review [114] 		Response (proportion of children very much improved or better) 12 weeks
55% with sertraline
24% with placebo
Absolute numbers not reported
OR 3.9
95% CI 2.1 to 7.4
P <0.001 		Moderate effect size sertraline
Open in a new tab

Quality of life

No data from the following reference on this outcome.[117] [114]

Adverse effects

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Adverse effects
[117]
RCT		 22 children and adolescents aged 5 to 17 years with childhood GAD
In review [114] 		Adverse effects
with sertraline (50 mg/day maximum)
with placebo		 Not significant
[107]
RCT
4-armed trial 		488 children aged 7 to 17 years with GAD or other anxiety disorders
In review [114] 		Adverse effects
with sertraline
with placebo
Absolute numbers not reported
P = 0.01 for insomnia
P = 0.003 for fatigue
P = 0.01 for sedation
P = 0.03 for restlessness 		Effect size not calculated placebo
Open in a new tab

Antidepressants versus CBT:

We found one RCT.[107]

Symptom severity

Sertraline compared with CBT Sertraline and CBT seem equally effective at increasing response at 12 weeks in children and adolescents with generalised and other anxiety disorders (moderate-quality evidence).

Ref (type) Population Outcome, Interventions Results and statistical analysis Effect size Favours
Symptom severity
[107]
RCT
4-armed trial 		488 children aged 7 to 17 years with generalised or other anxiety disorders Response (proportion of children very much improved or better) 12 weeks
55% with sertraline
60% with CBT
Absolute numbers not reported
P = 0.41 		Not significant
Open in a new tab

Quality of life

No data from the following reference on this outcome.[107]

Adverse effects

No data from the following reference on this outcome.[107]

Further information on studies

None.

Comment

Two additional RCTs[118] [119] add support to the results of the RCT comparing fluvoxamine versus placebo,[116] with the findings that fluvoxamine reduced somatic symptoms (e.g., 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 included participants with comorbid disorders such as depression. This may restrict the generalisability of the results.

General harms:

See review on depression in adults (drug and other physical treatments). One review of suicidality and antidepressant use in paediatric patients (most of whom were diagnosed with major depression) found a modest increase in suicide risk associated with antidepressants.[120] However, one meta-analysis of RCTs of second-generation antidepressants in the treatment of paediatric depressive and anxiety disorders found no completed suicides reported in the RCTs reviewed.[121] There have been warnings about the risks associated with using antidepressants in children. See review on depression in children and adolescents.

Substantive changes

Antidepressants in children and adolescents New evidence added.[107] [114] Categorisation unchanged (Trade-off between benefits and harms).

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Antipsychotics in children and adolescents

Summary

We found no RCT evidence on the effects of antipsychotics in children and adolescents.

Benefits and harms

Antipsychotics in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

BMJ Clin Evid. 2011 Oct 27;2011:1002.

Pregabalin in children and adolescents

Summary

We found no RCT evidence on the effects of pregabalin in children and adolescents.

Benefits and harms

Pregabalin in children and adolescents:

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

Further information on studies

None.

Comment

None.

Substantive changes

No new evidence

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