Abstract
Introduction
Generalised anxiety disorder (GAD) in a child or adolescent is excessive worry and tension about everyday events that the child or adolescent cannot control and that is expressed on most days for at least 6 months, to the extent that there is distress or difficulty in performing day-to-day tasks.
Methods and outcomes
We conducted a systematic overview, aiming to answer the following clinical question: What are the effects of pharmacological treatments for generalised anxiety disorder in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2014 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review).
Results
At this update, searching of electronic databases retrieved 949 studies. After deduplication and removal of conference abstracts, 417 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 310 studies and the further review of 107 full publications. Of the 107 full articles evaluated, one systematic review was added at this update. We performed a GRADE evaluation for six PICO combinations.
Conclusions
In this systematic overview, we categorised the efficacy for six interventions based on information about the effectiveness and safety of antidepressants, antipsychotics, benzodiazepines, buspirone, hydroxyzine, and pregabalin.
Key Points
Generalised anxiety disorder (GAD) is excessive worry and tension about everyday events that the child or adolescent cannot control and that is expressed on most days for at least 6 months, to the extent that there is distress or difficulty in performing day-to-day tasks.
The most common anxieties in children relate to the health of others.
GAD in children is highly comorbid, with only 14% of one survey not having a comorbid anxiety disorder.
Among adolescents the lifetime prevalence is 3%: if one relaxes the duration criteria to the last 3 months, the lifetime prevalence increases to 5%.
Cognitive behavioural therapy (CBT) is the best and most evidenced treatment for anxiety disorders. Please see our previous overview (see Generalised anxiety disorder) for further information on the evidence for CBT.
For this update, we have decided to focus on examining the evidence from RCTs and systematic reviews of RCTs for medications that have been suggested for use in GAD, either in children or in adolescents.
Most of the options that have been proposed have data suggesting that they may work in adults, but no such data are available for children.
We found limited RCT evidence regarding the efficacy of antidepressants for childhood GAD. SSRIs (e.g., fluvoxamine, fluoxetine, sertraline) have shown some promise, but antidepressants are associated with abdominal pain and nausea, an increase in initial suicidal ideation, and other adverse effects.
We found no RCT evidence on the effects of benzodiazepines, buspirone, hydroxyzine, pregabalin, or antipsychotics in children and adolescents.
Clinical context
General background
Generalized anxiety disorder (GAD) is overwhelming, chronic worry about many aspects of life. It affects about 1% of children and 3% of adolescents. In children, it often involves fears about the family and about performing well at school. Children with GAD often have difficulties coping in the home environment, with daily tasks and self-care.
Focus of the review
Cognitive behavioural therapy (CBT) is the best and most evidenced treatment for anxiety disorders. However, for this update, we have decided to focus instead on examining the evidence for medications that have been suggested for use in GAD, either in children or in adolescents. Please see our previous overview (see Generalised anxiety disorders), which included information on the evidence for CBT as well as evidence on interventions to treat GAD in adults.
Comments on evidence
There is some evidence that newer antidepressants such as serotonin re-uptake inhibitors (SSRIs) may help children and adolescents with GAD, but these have side effects. Most of the options that have been proposed have data suggesting that they may work in adults, but no such data are available for children.
Search and appraisal summary
The update literature search for this overview was carried out from the date of the last search, May 2011, to August 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. Searching of electronic databases retrieved 949 studies. After deduplication and removal of conference abstracts, 417 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 310 studies and the further review of 107 full publications. Of the 107 full articles evaluated, one systematic review was added at this update.
About this condition
Definition
Generalised anxiety disorder (GAD) is defined as excessive worry and tension about everyday events and problems that is not controllable and is expressed 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] In children, this worry frequently involves the health of others, but children with GAD are more likely to worry about performance at school and family matters than children with other anxiety disorders.[2] Only 14% of one survey did not have a comorbid anxiety disorder.[2] Children with GAD, either pure or comorbid, have little difference in adaptive functioning in school compared with healthy children without GAD, but show difficulties in adaptive functioning at home duties or self-care and in family relationships.[3]
Incidence/ Prevalence
A survey of children and adolescents aged 5 to 16 years in the UK in 2004 estimated that 0.7% had GAD (boys: 0.6%; girls: 0.8%).[4] The US National Replication survey included participants aged 13 to 18, who had a lifetime prevalence of GAD of 3%.[5]
Aetiology/ Risk factors
Little is known about the aetiology of GAD alone in children and adolescents. The fluidity of the diagnosis and the high rate of comorbidity has led some researchers to question if this is a valid entity in this group, or a temperamental state. This has been challenged by the demonstration of significant decreased function both in pure GAD and in comorbid GAD.[3]
Prognosis
There is a hypothesis that child and adolescent GAD either persists or is a risk factor for later anxiety disorders. The data for each condition, however, are lacking. It seems that having disorders or dysfunction in childhood predicts disorder in adolescents, and adolescent disorder increases risk for disorders in adults. The loading does not seem to be to any one disorder, but to either externalising or internalising factors, using a three- or two-item model[6] that seems to be robust into at least middle adulthood.[7] One has to approach this with caution: childhood GAD is much more comorbid, and may indeed be different from adult GAD.
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). 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 pre-treatment score; patient-rated improvement; failure to show a response. Quality of life; adverse effects.
Methods
Search strategy BMJ Clinical Evidence search and appraisal date August 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to August 2014, Embase 1980 to August 2014, The Cochrane Database of Systematic Reviews 2014, issue 8 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this systematic overview were systematic reviews and RCTs published in English, at least double-blinded, and containing 20 or more individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported question: What are the effects of treatments for generalised anxiety disorder in adults? We have amended the question on children and adolescents to focus on pharmacological therapies. Data and quality To aid readability of the numerical data in our overviews, 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). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. 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 in children and adolescents.
| 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 pharmacological treatments for generalised anxiety disorder in children and adolescents? | |||||||||
| 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 anxiety 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 anxiety 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 anxiety 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 anxiety disorders |
| 2 (231) | Symptom severity | Sertraline versus placebo | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of children with other anxiety disorders |
| 1 (272) | Symptom severity | Antidepressants versus CBT | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for inclusion of children with other anxiety disorders |
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
- 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.
- 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.
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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