Animal models of social anxiety disorder and their validity criteria

Anxiety disorders pose one of the largest threats to global mental health, and they predominantly emerge early in life. Social anxiety disorder, also known as social phobia, is the most common of all anxiety disorders. Moreover, it has severe consequences and is a disabling disorder that can cause an individual to be unable to perform the tasks of daily life. Social anxiety disorder is associated with the subsequent development of major depression and other mental diseases, as well as increased substance abuse. Although some neurobiological alterations have been found to be associated with social anxiety disorder, little is known about this disorder. Animal models are useful tools for the investigation of this disorder, as well as for finding new pharmacological targets for treatment. Thus, this review will highlight the main animal models of anxiety associated with social phobia.     

The Cost Effectiveness of Psychological and Pharmacological Interventions for Social Anxiety Disorder: A Model-Based Economic Analysis

Background

Social anxiety disorder is one of the most persistent and common anxiety disorders. Individually delivered psychological therapies are the most effective treatment options for adults with social anxiety disorder, but they are associated with high intervention costs. Therefore, the objective of this study was to assess the relative cost effectiveness of a variety of psychological and pharmacological interventions for adults with social anxiety disorder.

Methods

A decision-analytic model was constructed to compare costs and quality adjusted life years (QALYs) of 28 interventions for social anxiety disorder from the perspective of the British National Health Service and personal social services. Efficacy data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published literature and national sources, supplemented by expert opinion.

Results

Individual cognitive therapy was the most cost-effective intervention for adults with social anxiety disorder, followed by generic individual cognitive behavioural therapy (CBT), phenelzine and book-based self-help without support. Other drugs, group-based psychological interventions and other individually delivered psychological interventions were less cost-effective. Results were influenced by limited evidence suggesting superiority of psychological interventions over drugs in retaining long-term effects. The analysis did not take into account side effects of drugs.

Conclusion

Various forms of individually delivered CBT appear to be the most cost-effective options for the treatment of adults with social anxiety disorder. Consideration of side effects of drugs would only strengthen this conclusion, as it would improve even further the cost effectiveness of individually delivered CBT relative to phenelzine, which was the next most cost-effective option, due to the serious side effects associated with phenelzine. Further research needs to determine more accurately the long-term comparative benefits and harms of psychological and pharmacological interventions for social anxiety disorder and establish their relative cost effectiveness with greater certainty.     

Animal models of social avoidance and social fear

Social fear and avoidance of social situations represent the main behavioral symptoms of social anxiety disorder (SAD), a highly prevalent anxiety disorder that is poorly elucidated and has rather unsatisfactory therapeutic options. Therefore, animal models are needed to study the underlying etiology and pathophysiology of SAD and to verify the efficacy of possible novel treatment approaches. In this review, we describe and discuss the most important paradigms that have been shown to induce social avoidance and fear in rodents, including foot shock exposure, restraint stress, social isolation, social instability, social defeat, conditioned defeat, social defeat/overcrowding, chronic subordinate colony housing, chronic mild stress, maternal separation and social fear conditioning. We also describe some of the behavioral paradigms used to assess social avoidance and fear in rodents, including the social interaction test, the social preference-avoidance test, the social approach-avoidance test, the three-chambered social approach test, the partition test and the modified Y-maze test. We focus on the behavioral alterations these paradigms induce, especially on social interaction, general anxiety and depressive-like behavior given that SAD is strongly comorbid with anxiety and affective disorders.     

Role of corticotropin releasing factor in anxiety disorders: a translational research perspective

Anxiety disorders are a group of mental disorders that include generalized anxiety disorder (GAD), panic disorder, phobic disorders (e.g., specific phobias, agoraphobia, social phobia) and posttraumatic stress disorder (PTSD). Anxiety disorders are among the most common of all mental disorders and, when coupled with an awareness of the disability and reduced quality of life they convey, they must be recognized as a serious public health problem. Over 20 years of preclinical studies point to a role for the CRF system in anxiety and stress responses. Clinical studies have supported a model of CRF dysfunction in depression and more recently a potential contribution to specific anxiety disorders (i.e., panic disorder and PTSD). Much work remains in both the clinical and preclinical fields to inform models of CRF function and its contribution to anxiety. First, we will review the current findings of CRF and HPA axis abnormalities in anxiety disorders. Second, we will discuss startle reflex measures as a tool for translational research to determine the role of the CRF system in development and maintenance of clinical anxiety.     

Candidate biomarkers in psychiatric disorders: state of the field

The field of psychiatry is hampered by a lack of robust, reliable and valid biomarkers that can aid in objectively diagnosing patients and providing individualized treatment recommendations. Here we review and critically evaluate the evidence for the most promising biomarkers in the psychiatric neuroscience literature for autism spectrum disorder, schizophrenia, anxiety disorders and post-traumatic stress disorder, major depression and bipolar disorder, and substance use disorders. Candidate biomarkers reviewed include various neuroimaging, genetic, molecular and peripheral assays, for the purposes of determining susceptibility or presence of illness, and predicting treatment response or safety. This review highlights a critical gap in the biomarker validation process. An enormous societal investment over the past 50 years has identified numerous candidate biomarkers. However, to date, the overwhelming majority of these measures have not been proven sufficiently reliable, valid and useful to be adopted clinically. It is time to consider whether strategic investments might break this impasse, focusing on a limited number of promising candidates to advance through a process of definitive testing for a specific indication. Some promising candidates for definitive testing include the N170 signal, an event-related brain potential measured using electroencephalography, for subgroup identification within autism spectrum disorder; striatal resting-state functional magnetic resonance imaging (fMRI) measures, such as the striatal connectivity index (SCI) and the functional striatal abnormalities (FSA) index, for prediction of treatment response in schizophrenia; error-related negativity (ERN), an electrophysiological index, for prediction of first onset of generalized anxiety disorder, and resting-state and structural brain connectomic measures for prediction of treatment response in social anxiety disorder. Alternate forms of classification may be useful for conceptualizing and testing potential biomarkers. Collaborative efforts allowing the inclusion of biosystems beyond genetics and neuroimaging are needed, and online remote acquisition of selected measures in a naturalistic setting using mobile health tools may significantly advance the field. Setting specific benchmarks for well-defined target application, along with development of appropriate funding and partnership mechanisms, would also be crucial. Finally, it should never be forgotten that, for a biomarker to be actionable, it will need to be clinically predictive at the individual level and viable in clinical settings.     

Impairments in Goal-Directed Actions Predict Treatment Response to Cognitive-Behavioral Therapy in Social Anxiety Disorder

Social anxiety disorder is characterized by excessive fear and habitual avoidance of social situations. Decision-making models suggest that patients with anxiety disorders may fail to exhibit goal-directed control over actions. We therefore investigated whether such biases may also be associated with social anxiety and to examine the relationship between such behavior with outcomes from cognitive-behavioral therapy. Patients diagnosed with social anxiety and controls completed an instrumental learning task in which two actions were performed to earn food outcomes. After outcome devaluation, where one outcome was consumed to satiety, participants were re-tested in extinction. Results indicated that, as expected, controls were goal-directed, selectively reducing responding on the action that previously delivered the devalued outcome. Patients with social anxiety, however, exhibited no difference in responding on either action. This loss of a devaluation effect was associated with greater symptom severity and poorer response to therapy. These findings indicate that variations in goal-directed control in social anxiety may represent both a behavioral endophenotype and may be used to predict individuals who will respond to learning-based therapies.     

Salient components of a comprehensive service for eating disorders

Eating disorders are challenging and difficult to treat, because of the necessity of a multidisciplinary treatment team for effective outcomes and the high mortality rate of anorexia nervosa. An adequate initial assessment and evaluation requires a psychiatric assessment, a medical history and medical examination, a social history and an interview of family members or collateral informants. A comprehensive eating disorder treatment team includes a psychiatrist coordinating the treatment and appropriate medical physician specialists, nutritionists, and psychotherapists. An adequate outpatient eating disorder clinic needs to provide individual psychotherapy with cognitive behavioral techniques specific for anorexia nervosa and bulimia nervosa, family therapy, pharmacological treatment and the resources to obtain appropriate laboratory tests. Eating disorder patients requiring inpatient care are best treated in a specialized eating disorder inpatient unit. A cognitive behavioral framework is most useful for the overall unit milieu. Medical management and nutritional rehabilitation are the primary goals for inpatient treatment. Various group therapies can cover common core eating disorder psychopathology problems and dialectical behavior therapy groups can be useful for managing emotional dysregulation. Residential, partial hospitalization and day treatment programs are useful for transitioning patients from an inpatient program or for patients needing some monitoring. In these programs, at least one structured meal is advisable as well as nutritional counseling, group therapy or individual counseling sessions. Group therapies usually address issues such as social skills training, social anxiety, body image distortion or maturity fears. Unfortunately there is s paucity of evidence based randomized control trials to recommend the salient components for a comprehensive service for eating disorders. Experienced eating disorder clinicians have come to the conclusion that a multidisciplinary team approach provides the most effective treatment.     

Subtypes of Ataques de Nervios: The Influence of Coexisting Psychiatric Diagnosis

The current study assesses the relationship between presenting symptomatology of the self-labeled Hispanic popular diagnosis of ataques de nervios and the specific co-morbid psychiatric diagnoses. Hispanic subjects seeking treatment at an anxiety disorders clinic (n = 156) were assessed with a specially designed self-report instrument for both traditional ataque de nervios and panic symptoms, and with structured or semi-structured psychiatric interviews for Axis-I disorders. This report focuses on 102 subjects with ataque de nervios who also met criteria for panic disorder, other anxiety disorders, or an affective disorder. Distinct ataque symptom patterns correlated with co-existing panic disorder, affective disorders, or other anxiety disorders. Individuals with both ataque and panic disorder reported the most asphyxia, fear of dying, and increased fear during their ataques. People with ataques who also met criteria for affective disorder reported the most anger, screaming, becoming aggressive, and breaking things during ataques. Ataque positive subjects with other anxiety disorders were less salient for both panic-like and emotional-anger symptoms. The findings suggest that (a) ataque de nervios is a popular label referring to several distinct patterns of loss of emotional control, (b) the type of loss of emotional control is influenced by the associated psychiatric disorder, and (c) ataque symptom patterns may be a useful clinical marker for detecting psychiatric disorders. Further study is needed to examine the relationship between ataque de nervios and psychiatric disorders, as well as the relationship to cultural, demographic, environmental, and personality factors.     

Anxiété et personnalité: études catégorielle et dimensionnelle de leur association et facteurs de vulnérabilité

Anxiety disorders often appear in patients with particular personality traits, and in some cases with actual personality disorders. This clinical observation may question the respective interactions between personality and anxiety disorders: Is it possible to evaluate the personality of patients with severe anxiety disorders reliably? What is the real co-morbidity between personality disorders and anxiety disorders? Are there psychopathological and etiological links between these two disorders? Studies relying on categorical approaches of personality suggest that about 40-60% of anxious patients fulfill the diagnostic criteria of at least one personality disorder. The most frequent diagnoses belong to the cluster C of the DSM-IV axis II classification, with a majority having avoidant and dependent personalities, but without any real specificity according to the types of anxiety disorders. On the other hand, dimensional studies have shown that anxiety disorders are often associated with avoidant personality traits, with very deviant scores in some cases, even after treatment of the anxiety disorder. These works support the existence of some temperament traits, underlined by psychobiological, stable, and inheritable dimensions, which may constitute early vulnerability factors for anxiety disorders in both children and adults.     

The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies

Animal models and behavioral paradigms are critical for elucidating the neural mechanism involved in complex behaviors, including social cognition. Both genotype and phenotype based models have implicated the neuropeptide oxytocin (OT) in the regulation of social behavior. Based on the findings in animal models, alteration of the OT system has been hypothesized to play a role in the social deficits associated with autism and other neuropsychiatric disorders. While the evidence linking the peptide to the etiology of the disorder is not yet conclusive, evidence from multiple animal models suggest modulation of the OT system may be a viable strategy for the pharmacological treatment of social deficits. In this review, we will discuss how animal models have been utilized to understand the role of OT in social cognition and how those findings can be applied to the conceptualization and treatment of the social impairments in ASD. Animal models with genetic alterations of the OT system, like the OT, OT receptor and CD38 knock-out mice, and those with phenotypic variation in social behavior, like BTBR inbred mice and prairie voles, coupled with behavioral paradigms with face and construct validity may prove to have predictive validity for identifying the most efficacious methods of stimulating the OT system to enhance social cognition in humans. The widespread use of strong animal models of social cognition has the potential yield pharmacological, interventions for the treatment social impairments psychiatric disorders. This article is part of a Special Issue entitled Oxytocin, Vasopressin, and Social Behavior.     

Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus

We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies.     

Social conflict models: can they inform us about human psychopathology?

Social conflict models have been proposed as a powerful way to investigate basic questions of how brain and behavior are altered by social experience. Social defeat, in particular, appears to be a major stressor for most species, and in humans, this stressor is thought to play an important role in the onset of a variety of psychiatric disorders including depression and post-traumatic stress disorder. Aggressive experience, on the other hand, may promote disorders involving inappropriate aggression and violence. Current research using animal models of social conflict involves multiple levels of analysis from genetic and molecular to systems and overt behavior. This review briefly examines a variety of these animal models of social conflict in order to assess whether they are useful for advancing our understanding of how experience can shape brain and behavior and for translating this information so that we have the potential to improve the quality of life of individuals with mental illness and behavioral disorders.     

Reduced Heart Rate Variability in Social Anxiety Disorder: Associations with Gender and Symptom Severity

Background

Polyvagal theory emphasizes that autonomic nervous system functioning plays a key role in social behavior and emotion. The theory predicts that psychiatric disorders of social dysfunction are associated with reduced heart rate variability, an index of autonomic control, as well as social inhibition and avoidance. The purpose of this study was to examine whether heart rate variability was reduced in treatment-seeking patients diagnosed with social anxiety disorder, a disorder characterized by social fear and avoidance.

Methods

Social anxiety patients (n = 53) were recruited prior to receiving psychological therapy. Healthy volunteers were recruited through the University of Sydney and the general community and were matched by gender and age (n = 53). Heart rate variability was assessed during a five-minute recording at rest, with participants completing a range of self-report clinical symptom measures.

Results

Compared to controls, participants with social anxiety exhibited significant reductions across a number of heart rate variability measures. Reductions in heart rate variability were observed in females with social anxiety, compared to female controls, and in patients taking psychotropic medication compared to non-medicated patients. Finally, within the clinical group, we observed significant associations between reduced heart rate variability and increased social interaction anxiety, psychological distress, and harmful alcohol use.

Conclusions

The results of this study confirm that social anxiety disorder is associated with reduced heart rate variability. Resting state heart rate variability may therefore be considered a marker for social approach-related motivation and capacity for social engagement. Additionally, heart rate variability may provide a useful biomarker to explain underlying difficulties with social approach, impaired stress regulation, and behavioral inhibition, especially in disorders associated with significant impairments in these domains.     

Candidate genes for panic disorder: insight from human and mouse genetic studies

Panic disorder is a major cause of medical attention with substantial social and health service cost. Based on pharmacological studies, research on its etiopathogenesis has been focused on the possible dysfunction of specific neurotransmitter systems. However, recent work has related the genes involved in development, synaptic plasticity and synaptic remodeling to anxiety disorders. This implies that learning processes and changes in perception, interpretation and behavioral responses to environmental stimuli are essential for development of complex anxiety responses secondary to the building of specific brain neural circuits and to adult plasticity. The focus of this review is on progress achieved in identifying genes that confer increased risk for panic disorder through genetic epidemiology and the use of genetically modified mouse models. The integration of human and animal studies targeting behavioral, systems-level, cellular and molecular levels will most probably help identify new molecules with potential impact on the pathogenetic aspects of the disease.     

Anxiety disorders in nursing homes: a literature review of prevalence, course and risk indicators

Psychiatric disorders such as dementia and depression are highly prevalent in nursing homes. The prevalence of anxiety disorders is less clear. Prevalence, course and risk-indicators of anxiety disorders among nursing home residents were examined, based on a review of the literature. Medline and PsychINFO searches were conducted for 1966-2002. Twelve studies were considered relevant. These differed substantially with respect to study-population, diagnostic instruments and diagnostic criteria that were used and the specific anxiety disorders investigated. The prevalence of anxiety disorders ranged from 0-20%. Only in one study the course of anxiety disorders was investigated. About 60% of the nursing home residents recovered in one year. The most important risk-indicators for anxiety disorders identified were: female sex, depression, lack of social support, poor physical health and functional and cognitive impairments. Generalization of these results to the Dutch nursing home population is restricted by the substantial heterogeneity of the studies. Further studies are required to provide reliable estimates of prevalence, course and risk-indicators of anxiety disorders among nursing home residents using appropriate diagnostic instruments and adjusted diagnostic criteria. This will enhance detection and improve treatment of anxiety disorders among nursing home residents.     

Learning, climate and the evolution of cultural capacity

Patterns of environmental variation influence the utility, and thus evolution, of different learning strategies. I use stochastic, individual-based evolutionary models to assess the relative advantages of 15 different learning strategies (genetic determination, individual learning, vertical social learning, horizontal/oblique social learning, and contingent combinations of these) when competing in variable environments described by 1/f noise. When environmental variation has little effect on fitness, then genetic determinism persists. When environmental variation is large and equal over all time-scales ("white noise") then individual learning is adaptive. Social learning is advantageous in "red noise" environments when variation over long time-scales is large. Climatic variability increases with time-scale, so that short-lived organisms should be able to rely largely on genetic determination. Thermal climates usually are insufficiently red for social learning to be advantageous for species whose fitness is very determined by temperature. In contrast, population trajectories of many species, especially large mammals and aquatic carnivores, are sufficiently red to promote social learning in their predators. The ocean environment is generally redder than that on land. Thus, while individual learning should be adaptive for many longer-lived organisms, social learning will often be found in those dependent on the populations of other species, especially if they are marine. This provides a potential explanation for the evolution of a prevalence of social learning, and culture, in humans and cetaceans.     

Mood and anxiety disorders in women with PCOS

Women with polycystic ovary syndrome have gynecologic, reproductive and metabolic co-morbidities that span their entire lifespan. More recently a higher risk of mood and anxiety disorders has been reported in women with PCOS. Women with PCOS have higher depression scores and a higher risk of depression independent of BMI. Although clinical features of hyperandrogenism affect health related quality of life, the association between hirsutism, acne, body image and depression is currently unclear. Similarly there is limited data on the association between variables such as biochemical hyperandrogenism or infertility and depression. Women with PCOS are also at risk for symptoms of generalized anxiety disorder. There is insufficient data examining the risk of other anxiety disorders such as social phobia, obsessive compulsive disorders and panic disorder. In a number of patients some of these disorders coexist increasing the health burden. These data underscore the need to screen all women with PCOS for mood and anxiety disorders and adequately treat women who are diagnosed with these conditions.     

ComorbiditéS associées au trouble déficit de l’attention avec hyperactivité : Données épidémiologiques et implications thérapeutiques

ADHD has become one of the most frequent cause of referrals for children’ behaviour disorders. ADHD is a prevalent psychiatric condition affecting 5% to 9% of school-age children with regards to DSM-IV R diagnostic criteria. In addition, according to the results of different epidemiological studies, patients with ADHD very often experience comorbid conditions in 50% to 90% of the cases. The most frequent comorbidities include externalised disorders, (oppositional defiant disorder, conduct disorders), learning disorders, internalised disorders (anxiety, depression) and tics (chronic motor tics, Tourette’s syndrome). Given their negative impact on the outcome of ADHD in terms of affective and social functioning, and of social and school adaptation, these comorbid conditions should be carefully and systematically searched, even without any actual complaint. Although management of comorbid psychiatric conditions is never simple nor straightforward, therapeutic option should be considered taking into consideration both management of ADHD and specificity of these comorbidities.     

The prevalence and correlates of DSM-IV disorders in the Iraq Mental Health Survey (IMHS)

Data on the prevalence and correlates of anxiety, mood, behavioral, and substance disorders are presented from a 2007-8 national survey of the Iraq population, the Iraq Mental Health Survey (IMHS). The IMHS was carried out by the Iraq Ministry of Health in collaboration with the Iraq Ministry of Planning and the World Health Organization (WHO) World Mental Health (WMH) Survey Initiative. Interviews were administered to a probability sample of Iraqi household residents by trained lay interviewers. The WHO Composite International Diagnostic interview (CIDI) was used to assess DSM-IV disorders. The response rate was 95.2%. The estimated lifetime prevalence of any disorder was 18.8%. Cohort analysis documented significantly increasing lifetime prevalence of most disorders across generations. This was most pronounced for panic disorder and post-traumatic stress disorder, with lifetime-to-date prevalence 5.4-5.3 times as high at comparable ages in the youngest (ages 18-34) as oldest (ages 65+) cohorts. Anxiety disorders were the most common class of disorders (13.8%) and major depressive disorder (MDD) the most common disorder (7.2%). Twelve-month prevalence of any disorder was 13.6%, with 42.1% of cases classified mild, 36.0% moderate, and 21.9% serious. The disorders most often classified serious were bipolar disorder (76.9%) and substance-related disorders (54.9%). Socio-demographic correlates were generally consistent with international epidemiological surveys, with the two exceptions of no significant gender differences in mood disorders and positive correlations of anxiety and mood disorders with education. Only 2.2% of IMHS respondents reported receiving treatment for emotional problems in the 12 months before interview, including 23.7% of those with serious, 9.2% with moderate, and 5.3% with mild disorders and 0.9% of other respondents. Most healthcare treatment, which was roughly equally distributed between the general medical and specialty sectors, was of low intensity. Further analyses of barriers to seeking treatment are needed to inform government efforts to expand the detection and treatment of mental disorders     

How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta‐analytic update of the evidence

We report the current best estimate of the effects of cognitive behavior therapy (CBT) in the treatment of major depression (MDD), generalized anxiety disorder (GAD), panic disorder (PAD) and social anxiety disorder (SAD), taking into account publication bias, the quality of trials, and the influence of waiting list control groups on the outcomes. In our meta‐analyses, we included randomized trials comparing CBT with a control condition (waiting list, care‐as‐usual or pill placebo) in the acute treatment of MDD, GAD, PAD or SAD, diagnosed on the basis of a structured interview. We found that the overall effects in the 144 included trials (184 comparisons) for all four disorders were large, ranging from g=0.75 for MDD to g=0.80 for GAD, g=0.81 for PAD, and g=0.88 for SAD. Publication bias mostly affected the outcomes of CBT in GAD (adjusted g=0.59) and MDD (adjusted g=0.65), but not those in PAD and SAD. Only 17.4% of the included trials were considered to be high‐quality, and this mostly affected the outcomes for PAD (g=0.61) and SAD (g=0.76). More than 80% of trials in anxiety disorders used waiting list control groups, and the few studies using other control groups pointed at much smaller effect sizes for CBT. We conclude that CBT is probably effective in the treatment of MDD, GAD, PAD and SAD; that the effects are large when the control condition is waiting list, but small to moderate when it is care‐as‐usual or pill placebo; and that, because of the small number of high‐quality trials, these effects are still uncertain and should be considered with caution.