Anxiety Disorders in Older Adults a Comprehensive Review
Diagnosis and Direction of Generalized Anxiety Disorder and Panic Disorder in Adults
Am Fam Physician. 2015 May 1;91(9):617-624.
Patient information: See related handout on feet and panic disorders, written past the authors of this commodity.
This clinical content conforms to AAFP criteria for continuing medical instruction (CME). See the CME Quiz Questions.
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Commodity Sections
- Abstruse
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Treatment
- Referral and Prevention
- References
Generalized anxiety disorder (GAD) and panic disorder (PD) are among the well-nigh common mental disorders in the United States, and they can negatively impact a patient's quality of life and disrupt important activities of daily living. Evidence suggests that the rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms oftentimes ascribed to physical causes. Diagnosing GAD and PD requires a broad differential and caution to place misreckoning variables and comorbid conditions. Screening and monitoring tools can be used to help make the diagnosis and monitor response to therapy. The GAD-7 and the Severity Mensurate for Panic Disorder are gratuitous diagnostic tools. Successful outcomes may require a combination of treatment modalities tailored to the individual patient. Treatment often includes medications such as selective serotonin reuptake inhibitors and/or psychotherapy, both of which are highly constructive. Among psychotherapeutic treatments, cognitive beliefs therapy has been studied widely and has an extensive testify base of operations. Benzodiazepines are effective in reducing feet symptoms, but their use is limited by risk of abuse and agin event profiles. Physical activeness can reduce symptoms of GAD and PD. A number of complementary and culling treatments are oftentimes used; even so, prove is limited for most. Several common botanicals and supplements can potentiate serotonin syndrome when used in combination with antidepressants. Medication should be continued for 12 months before tapering to prevent relapse.
Generalized anxiety disorder (GAD) and panic disorder (PD) are amongst the most common mental disorders in the The states and are oft encountered past primary care physicians. The authentication of GAD is excessive, out-of-control worry, and PD is characterized by recurrent and unexpected panic attacks. Both conditions can negatively touch on a patient's quality of life and disrupt of import activities of daily living. The rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms often ascribed to physical causes.
This article reviews the diagnosis and direction of GAD and PD in adults. Diagnosis and care of children and adolescents with these weather condition require special considerations that are beyond the telescopic of this review.
SORT: KEY RECOMMENDATIONS FOR Do
| Clinical recommendation | Evidence rating | References |
|---|---|---|
| Physical activity is a cost-effective treatment for GAD and PD. | B | xvi, 17 |
| Selective serotonin reuptake inhibitors are considered first-line therapy for GAD and PD. | B | 19, 20, 22 |
| To avoid relapse, medication should exist connected for 12 months after symptoms ameliorate earlier tapering. | C | 11 |
| When used in combination with antidepressants, benzodiazepines may speed recovery from feet-related symptoms but exercise not improve longer-term outcomes. Because benzodiazepines are associated with tolerance, they should be used merely short term during crises. | B | xi, 28–30 |
| Psychotherapy can exist as constructive as medication for GAD and PD. Cognitive behavior therapy has the best level of evidence. | A | 11, 37 |
| Successful treatment requires tailoring options to individuals and may frequently include a combination of modalities. | C | 11, 37, 42 |
Epidemiology, Etiology, and Pathophysiology
- Abstruse
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Handling
- Referral and Prevention
- References
The 12-month prevalence for GAD and PD among U.Southward. adults xviii to 64 years of age is 2.9% and 3.i%, respectively. In this population, the lifetime prevalence is vii.seven% in women and 4.half dozen% in men for GAD, and is 7.0% in women and three.iii% in men for PD.1
The etiology of GAD is not well understood. There are several theoretical models, each with varying degrees of empirical support. An underlying theme to several models is the dysregulation of worry. Emerging show suggests that patients with GAD may experience persistent activation of areas of the encephalon associated with mental activity and introspective thinking post-obit worry-inducing stimuli.two Twin studies propose that environmental and genetic factors are likely involved.3
The etiology of PD is too not well understood. The neuroanatomical hypothesis suggests that a genetic-environment interaction is probable responsible. Patients with PD may showroom irregularities in specific brain structures, altered neuronal processes, and dysfunctional corticolimbic interaction during emotional processing.4
Typical Presentation and Diagnostic Criteria
- Abstruse
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Handling
- Referral and Prevention
- References
GENERALIZED Anxiety DISORDER
Patients with GAD typically nowadays with excessive feet about ordinary, mean solar day-today situations. The anxiety is intrusive, causes distress or functional damage, and often encompasses multiple domains (e.grand., finances, piece of work, health). The anxiety is often associated with concrete symptoms, such every bit sleep disturbance, restlessness, muscle tension, gastrointestinal symptoms, and chronic headaches.five Diagnostic and Statistical Manual of Mental Disorders, 5th ed, (DSM-five) diagnostic criteria for GAD are listed in Tabular array one.v Some factors associated with GAD include female sex, unmarried status, lower education level, poor health, and presence of life stressors.vi The historic period of onset is variable, with a median age of 30 years.ane
Table 1.
Diagnostic Criteria for Generalized Anxiety Disorder
| A. Excessive anxiety and worry (humble expectation), occurring more days than not for at least half dozen months, about a number of events or activities (such as piece of work or school performance). | |
| B. The private finds it difficult to control the worry. | |
| C. The anxiety and worry are associated with three (or more than) of the following six symptoms (with at least some symptoms having been nowadays for more days than not for the past 6 months): | |
| Note: Only one particular is required in children. | |
| ane. Restlessness or feeling keyed up or on border. | |
| 2. Being easily fatigued. | |
| 3. Difficulty concentrating or mind going bare. | |
| 4. Irritability. | |
| 5. Musculus tension. | |
| 6. Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep). | |
| D. The anxiety, worry, or concrete symptoms crusade clinically meaning distress or impairment in social, occupational, or other important areas of functioning. | |
| Due east. The disturbance is not attributable to the physiological furnishings of a substance (eastward.one thousand., a drug of abuse, a medication) or some other medical condition (e.chiliad., hyperthyroidism). | |
| F. The disturbance is not amend explained by another mental disorder (e.m., feet or worry virtually having panic attacks in panic disorder, negative evaluation in social anxiety disorder [social phobia], contagion or other obsessions in obsessive-compulsive disorder, separation from attachment figures in separation anxiety disorder, reminders of traumatic events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physical complaints in somatic symptom disorder, perceived advent flaws in trunk dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional behavior in schizophrenia or delusional disorder). | |
A number of scales are available to establish diagnosis and assess severity. The GAD-seven (Table ii7) has been validated as a diagnostic tool and a severity assessment scale, with a score of 10 or more having practiced diagnostic sensitivity and specificity.8 Greater GAD-seven scores correlate with more functional damage.8 The scale was developed and validated based on DSM-4 criteria, just it remains clinically useful after publication of the DSM-5 because the differences in GAD diagnostic criteria are minimal. The PRO-MIS Emotional Distress–Feet–Curt Form for adults and the Severity Measure for Generalized Anxiety Disorder–Adult, bachelor from the American Psychiatric Clan at http://world wide web.psychiatry.org/practice/dsm/dsm5/online-assessment-measures, are intended to assist clinical evaluation of GAD and monitor treatment effectiveness.
Table 2.
GAD-vii Screening Tool
| Over the last 2 weeks, how often have yous been bothered by the post-obit problems? | Not at all | Several days | More than one-half the days | Nearly every day |
|---|---|---|---|---|
| (Apply "✓" to indicate your answer) | ||||
| 1. Feeling nervous, anxious, or on edge | 0 | 1 | 2 | iii |
| 2. Not beingness able to finish or control worrying | 0 | ane | 2 | 3 |
| three. Worrying too much about different things | 0 | 1 | ii | 3 |
| iv. Trouble relaxing | 0 | ane | 2 | three |
| 5. Being so restless that it is hard to sit however | 0 | 1 | ii | 3 |
| 6. Condign hands annoyed or irritable | 0 | 1 | 2 | 3 |
| 7. Feeling agape as if something atrocious might happen | 0 | i | 2 | three |
| Total score_____ | =___ | +___ | +___ | +___ |
PANIC DISORDER
PD is characterized past episodic, unexpected panic attacks that occur without a clear trigger.5 Panic attacks are defined by the rapid onset of intense fearfulness (typically peaking within about 10 minutes) with at least four of the physical and psychological symptoms in the DSM-five diagnostic criteria (Table 3).5 Some other requirement for the diagnosis of PD is that the patient worries about farther attacks or modifies his or her behavior in maladaptive ways to avert them. The most mutual physical symptom accompanying panic attacks is palpitations.9 Although unexpected panic attacks are required for the diagnosis, many patients with PD also have expected panic attacks, occurring in response to a known trigger.nine The Severity Mensurate for Panic Disorder–Adult (http://www.psychiatry.org/File%20Library/Practise/DSM/DSM-v/SeverityMeasureForPanicDisorderAdult.pdf) is an assessment scale that tin complement the clinical assessment of patients with PD.
Table 3.
Diagnostic Criteria for Panic Disorder
| A. Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and during which time four (or more) of the following symptoms occur: | |
| Notation: The sharp surge can occur from a calm state or an anxious state. | |
| ane. Palpitations, pounding heart, or accelerated center rate. | |
| ii. Sweating. | |
| 3. Trembling or shaking. | |
| four. Sensations of shortness of breath or smothering. | |
| five. Feelings of choking. | |
| six. Breast pain or discomfort. | |
| vii. Nausea or abdominal distress. | |
| 8. Feeling empty-headed, unsteady, lightheaded, or faint. | |
| 9. Chills or oestrus sensations. | |
| 10. Paresthesias (numbness or tingling sensations). | |
| 11. Derealization (feelings of unreality) or depersonalization (being discrete from oneself). | |
| 12. Fear of losing control or "going crazy." | |
| 13. Fright of dying. | |
| Annotation: Culture-specific symptoms (e.thou., tinnitus, cervix soreness, headache, uncontrollable screaming or crying) may be seen. Such symptoms should not count equally i of the four required symptoms. | |
| B. At least one of the attacks has been followed past 1 calendar month (or more) of one or both of the following: | |
| 1. Persistent business or worry most additional panic attacks or their consequences (due east.k., losing control, having a centre attack, "going crazy"). | |
| 2. A meaning maladaptive change in behavior related to the attacks (e.g., behaviors designed to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations). | |
| C. The disturbance is not attributable to the physiological furnishings of a substance (due east.g., a drug of corruption, a medication) or another medical condition (e.g., hyperthyroidism, cardiopulmonary disorders). | |
| D. The disturbance is not better explained by another mental disorder (e.yard., the panic attacks do not occur only in response to feared social situations, equally in social anxiety disorder; in response to circumscribed phobic objects or situations, as in specific phobia; in response to obsessions, equally in obsessive-compulsive disorder; in response to reminders of traumatic events, as in posttraumatic stress disorder; or in response to separation from attachment figures, as in separation anxiety disorder). | |
Differential Diagnosis and Comorbidity
- Abstract
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Handling
- Referral and Prevention
- References
When evaluating a patient for a suspected anxiety disorder, it is of import to exclude medical conditions with similar presentations (e.thou., endocrine conditions such every bit hyperthyroidism, pheochromocytoma, or hyperparathyroidism; cardiopulmonary atmospheric condition such as arrhythmia or obstructive pulmonary diseases; neurologic diseases such as temporal lobe epilepsy or transient ischemic attacks). Other psychiatric disorders (e.g., other feet disorders, major depressive disorder, bipolar disorder); apply of substances such as caffeine, albuterol, levothyroxine, or decongestants; or substance withdrawal may also present with like symptoms and should exist ruled out.5
Complicating the diagnosis of GAD and PD is that many conditions in the differential diagnosis are also common comorbidities. Additionally, many patients with GAD or PD meet criteria for other psychiatric disorders, including major depressive disorder and social phobia. Evidence suggests that GAD and PD unremarkably occur with at least one other psychiatric disorder, such every bit mood, anxiety, or substance utilize disorders.ten When anxiety disorders occur with other conditions, historic, physical, and laboratory findings may be helpful in distinguishing each diagnosis and developing appropriate treatment plans.
Treatment
- Abstract
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Treatment
- Referral and Prevention
- References
Some studies evaluating feet treatments assess non-specific feet-related symptoms rather than the ready of symptoms that characterize GAD or PD. When possible, the treatments described in this department volition differentiate between GAD and PD; otherwise, treatments refer to anxiety-related symptoms in full general.
Medication or psychotherapy is a reasonable initial treatment option for GAD and PD.11 Some studies suggest that combining medication and psychotherapy may be more effective for patients with moderate to severe symptoms.12 The National Plant for Wellness and Care Excellence (Dainty) guidelines on GAD and PD in adults are a useful review of available evidence; however, data near cocky-help and group therapies may accept less utility in the U.s. because of their relative lack of availability.eleven
EDUCATION
Empathetic listening and education are an of import foundation in the treatment of anxiety disorders.eleven Patient education itself tin help reduce anxiety, peculiarly in PD.xiii The establishment of a therapeutic alliance between the patient and physician is important to abate fears of interventions and to progress toward handling.
Common lifestyle recommendations that may reduce anxiety-related symptoms include identifying and removing possible triggers (east.g., caffeine, stimulants, nicotine, dietary triggers, stress), and improving slumber quality/quantity and physical activity.
Caffeine tin can trigger PD and other types of anxiety. Those with PD may exist more sensitive to caffeine than the general population considering of genetic polymorphisms in adenosine receptors.14 Smoking abeyance leads to improved anxiety scores, with relapse leading to increased anxiety. Many studies evidence an association between matted sleep and anxiety, just causality is unclear.15 In addition to decreased depression and anxiety, physical action is associated with improved physical health, life satisfaction, cognitive functioning, and psychological well-being. Physical activity is a cost-effective arroyo in the treatment of GAD and PD.16,17 Exercising at lx% to ninety% of maximal center rate for 20 minutes iii times weekly has been shown to decrease anxiety16; yoga is likewise effective.eighteen
MEDICATION
First-Line Therapies. A number of medications are available for treating anxiety (Tabular array 4). Selective serotonin reuptake inhibitors (SSRIs) are mostly considered first-line therapy for GAD and PD.19–22 Tricyclic antidepressants (TCAs) are better studied for PD, simply are idea to be constructive for both GAD and PD.nineteen,20 In the treatment of PD, TCAs are every bit effective as SSRIs, only adverse effects may limit the employ of TCAs in some patients.23 Venlafaxine, extended release, is constructive and well tolerated for GAD and PD, whereas duloxetine (Cymbalta) has been fairly evaluated only for GAD.24 Azapirones, such every bit buspirone (Buspar), are better than placebo for GAD25 but do non appear to be effective for PD.26 Mixed bear witness suggests bupropion (Wellbutrin) may accept anxiogenic furnishings for some patients, thus warranting close monitoring if used for treatment of comorbid depression, seasonal melancholia disorder, or smoking cessation.27 Bupropion is non approved for the handling of GAD or PD.
Tabular array iv.
Medications for the Handling of Generalized Anxiety Disorder and Panic Disorder
| Medication | Estimated cost* | |
|---|---|---|
| First line | ||
| Selective serotonin reuptake inhibitors | ||
| Escitalopram (Lexapro) | $25 ($190) | |
| Fluoxetine (Prozac) | $v ($250) | |
| Fluvoxamine for PD | $15 (NA) | |
| Paroxetine (Paxil) | $5 ($150) | |
| Sertraline (Zoloft) | $10 ($200) | |
| Serotonin-norepinephrine reuptake inhibitors | ||
| Duloxetine (Cymbalta) for GAD | $50 ($210) | |
| Venlafaxine, extended release (Effexor XR) | $15 ($230) | |
| Azapirone | ||
| Buspirone (Buspar) for GAD | $v ($87) | |
| 2d line | ||
| Tricyclic antidepressants | ||
| Amitriptyline† | $5 (NA) | |
| Imipramine (Tofranil)‡ | $ten ($265) | |
| Nortriptyline (Pamelor)† | $x ($725) | |
| Antiepileptics | ||
| Pregabalin (Lyrica)† for GAD | NA ($145) | |
| Antipsychotics | ||
| Quetiapine (Seroquel)† for GAD | $15 ($130) | |
| Hydroxyzine (Vistaril) | $12 ($200) | |
| Third line | ||
| Monoamine oxidase inhibitors§ | ||
| Isocarboxazid (Marplan)† | NA ($130) | |
| Phenelzine (Nardil)† | $20 ($50) | |
| Tranylcypromine (Parnate)† | $50 ($185) | |
| Augmentation | ||
| Benzodiazepines|| | ||
| Alprazolam (Xanax) ¶ | $10 ($70) | |
| Clonazepam (Klonopin)** | $10 ($lxx) | |
| Diazepam (Valium) for GAD | $10 ($90) | |
| Lorazepam (Ativan)‡ | $x ($300) | |
Medications should be titrated slowly to decrease the initial activation. Because of the typical delay in onset of action, medications should not exist considered ineffective until they are titrated to the loftier end of the dose range and continued for at to the lowest degree four weeks. Once symptoms have improved, medications should be used for 12 months before tapering to limit relapse.11 Some patients will require longer handling.
Benzodiazepines are effective in reducing anxiety, merely in that location is a dose-response human relationship associated with tolerance, sedation, confusion, and increased mortality.28 When used in combination with antidepressants, benzodiazepines may speed recovery from anxiety-related symptoms but do not better longer-term outcomes. The higher risk of dependence and agin outcomes complicates the use of benzodiazepines.29 NICE guidelines recommend only short-term use during crises.xi Benzodiazepines with an intermediate to long onset of action (such as clonazepam [Klonopin]) may have less potential for corruption and less gamble of rebound.30
Second-Line Therapies. Second-line therapies for GAD include pregabalin (Lyrica) and quetiapine (Seroquel), although neither has been evaluated for PD. Pregabalin is more than effective than placebo but not as effective as lorazepam (Ativan) for GAD. Weight gain is a common adverse effect of pregabalin. There is limited evidence for the utilise of antipsychotics to care for anxiety disorders. Although quetiapine seems to be effective for GAD, the adverse effect contour is significant, including weight gain, diabetes mellitus, and hyperlipidemia.31 Hydroxyzine is considered a second-line treatment for GAD,32 simply in that location are minimal data for its apply in PD. Its rapid onset tin exist appealing for patients needing immediate relief, and it may be a more advisable alternative if benzodiazepines are contraindicated (e.g., in patients with a history of substance abuse). Based on clinical feel, gabapentin (Neurontin) is sometimes prescribed by psychiatrists to treat anxiety on an as-needed basis when benzodiazepines are contraindicated. Of notation, the placebo response for medications used to treat GAD and PD is high.13
PSYCHOTHERAPY AND RELAXATION THERAPIES
Psychotherapy includes many different approaches, such as cerebral beliefs therapy (CBT) and applied relaxation (Tabular array 5).33,34 CBT may use applied relaxation, exposure therapy, breathing, cognitive restructuring, or educational activity. Psychotherapy is as effective as medication for GAD and PD.11 Although existing evidence is insufficient to draw conclusions nigh many psychotherapeutic interventions, structured CBT interventions take consistently proven constructive for the treatment of feet in the primary care setting.34–36 Psychotherapy may be used solitary or combined with medication as first-line treatment for PD37 and GAD,11 based on patient preference. Psychotherapy should be performed weekly for at least eight weeks to assess its effect.
Table v.
Possible Beliefs Interventions for the Treatment of Generalized Anxiety Disorder, Panic Disorder, and Anxiety-Related Symptoms
| Intervention | Comments |
|---|---|
| Cognitive beliefs therapy* | This intervention is useful in treating feet disorders. The cognitive portion assists change in thinking patterns that back up fears, whereas the behavior portion often involves training patients to relax deeply and helps desensitize patients to anxiety-provoking triggers. |
| To be constructive, therapy must exist directed at the patient's specific anxieties and tailored to his or her needs. There are minimal adverse furnishings, except that behavior desensitization is typically associated with temporary mild increases in anxiety.33 | |
| Mindfulness-based stress reduction† | This intervention promotes focused attending on the present, acknowledgment of 1'south emotional state, and meditation for farther stress reduction and relaxation. |
| Key features include moment to moment sensation cultivated with a nonjudgmental attitude, formal meditation techniques, and daily practice.34 |
Mindfulness has similar effectiveness to traditional CBT or other behavior therapies,38 particularly mindfulness-based stress reduction.39 A meta-assay of 36 randomized controlled trials on meditation showed that meditative therapies reduce anxiety symptoms, but nigh studies looked at anxiety symptoms rather than feet disorders.xl Transcendental meditation has similar effectiveness to other relaxation therapies.41
After a treatment course, rebound symptoms may occur less often with psychotherapy than with medications. Successful treatment requires tailoring options to individuals and may ofttimes include a combination of modalities.11,37,42 Combined treatment with medications and psychotherapy reduces relapse fifty-fifty at 2 years.43
COMPLEMENTARY AND ALTERNATIVE MEDICINE THERAPIES
Although a number of complementary and culling products accept bear witness for treating low, almost lack sufficient show for the treatment of anxiety. Botanicals and supplements sometimes used to care for GAD and PD are listed in Tabular array 6. Kava extract is an effective treatment for anxiety 44; notwithstanding, case reports of hepatotoxicity have decreased its use.45 St. John'due south wort, tryptophan, 5-Hydroxytryptophan, and South-adenosyl-50-methionine should exist used with caution in combination with SSRIs because of the increased chance of serotonin syndrome.46
Bear witness indicates that music therapy, aromatherapy, acupuncture, and massage are helpful for anxiety associated with specific affliction states, but none take been evaluated specifically for GAD or PD.
Tabular array vi.
Botanicals and Supplements Sometimes Used to Treat Generalized Anxiety Disorder and Panic Disorder
| Therapy | Potential significant agin effects* |
|---|---|
| Botanicals | |
| Kava (Piper methysticum) | Possible hepatotoxicity, sedation, interference with P450 substrates |
| Lavender oil (Lavandula angustifolia) | Minimal |
| Passionflower (Passiflora incarnata) | Dizziness, sedation, decreased blood pressure |
| St. John'due south wort (Hypericum perforatum)† | Similar to serotonin reuptake inhibitors, interference with P450 substrates |
| Valerian (Valeriana officinalis) | Headache, gastrointestinal upset |
| Supplements | |
| 5-Hydroxytryptophan† | Gastrointestinal upset, possible eosinophilia-myalgia syndrome |
| Inositol | Nausea, headache |
| l-theanine | May lower blood force per unit area; may lower effect of stimulant medication |
| l-tryptophan† | Gastrointestinal upset, possible eosinophilia-myalgia syndrome |
| Southward-adenosyl-fifty-methionine† | Gastrointestinal upset, mania in patients with bipolar disorder |
| Vitamin B complex | Yellow urine |
Referral and Prevention
- Abstract
- Epidemiology, Etiology, and Pathophysiology
- Typical Presentation and Diagnostic Criteria
- Differential Diagnosis and Comorbidity
- Treatment
- Referral and Prevention
- References
For patients with GAD or PD, psychiatric referral may be indicated if there is poor response to treatment, atypical presentation, or concern for significant comorbid psychiatric illness. In that location is insufficient show to back up a concise recommendation on the prevention of PD and GAD in adults.
Data Sources: We searched Essential Testify Plus, PubMed, and Ovid Medline using the keywords generalized anxiety disorder, panic disorder, diagnosis, handling, medication, epidemiology, etiology, pathophysiology, differential diagnosis, and complementary and alternative medicine. We searched professional and authoritative organizations on the topic of feet disorders, including the American Psychological Association, the National Institute of Mental Wellness, the National Constitute for Health and Care Excellence, and the Cochrane Collaboration. Search dates: May to July 2014.
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