Anxiety Disorders
Anxiety Disorders
Anxiety Disorders
Anxiety disorders
Brenda W J H Penninx, Daniel S Pine, Emily A Holmes, Andreas Reif
Lancet 2021; 397: 914–27 Anxiety disorders form the most common group of mental disorders and generally start before or in early adulthood.
Published Online Core features include excessive fear and anxiety or avoidance of perceived threats that are persistent and impairing.
February 11, 2021 Anxiety disorders involve dysfunction in brain circuits that respond to danger. Risk for anxiety disorders is influenced
https://doi.org/10.1016/
by genetic factors, environmental factors, and their epigenetic relations. Anxiety disorders are often comorbid
S0140-6736(21)00359-7
with one another and with other mental disorders, especially depression, as well as with somatic disorders. Such
This online publication has been
corrected. The corrected version comorbidity generally signifies more severe symptoms, greater clinical burden, and greater treatment difficulty.
first appeared at thelancet.com Reducing the large burden of disease from anxiety disorders in individuals and worldwide can be best achieved by
on March 4, 2021 timely, accurate disease detection and adequate treatment administration, scaling up of treatments when needed.
Department of Psychiatry, Evidence-based psychotherapy (particularly cognitive behavioural therapy) and psychoactive medications (particularly
Amsterdam University Medical serotonergic compounds) are both effective, facilitating patients’ choices in therapeutic decisions. Although
Center, Vrije Universiteit,
Amsterdam, Netherlands
promising, no enduring preventive measures are available, and, along with frequent therapy resistance, clinical needs
(Prof B W J H Penninx PhD); remain unaddressed. Ongoing research efforts tackle these problems, and future efforts should seek individualised,
GGZ inGeest, Amsterdam, more effective approaches for treatment with precision medicine.
Netherlands
(Prof B W J H Penninx); Emotion
and Development Branch,
Introduction fears and anxieties represent normative occurrences
National Institute of Mental Anxiety disorders form the most common type of mental in childhood (eg, stranger or performance anxiety) or in
Health, Bethesda, MD, USA illness. Anxiety disorders comprise separation anxiety adulthood (eg, anxiety during life stress or transitions).
(Prof D S Pine MD); Department
and selective mutism (occurring primarily in childhood; Fears and anxieties can require clinical attention
of Psychology, Uppsala
University, Uppsala, Sweden between the ages of 4 years and 18 years), specific phobias, when they are disproportionate to a threat, are severe and
(Prof E A Holmes PhD); social anxiety disorder, and generalised anxiety disorder enduring, or disrupt normal functioning. Perceived
Department of Psychiatry, (occurring in childhood as well as in adulthood), as well as threats include environmental stimuli (eg, a social
Psychosomatic Medicine and
panic disorder and agoraphobia (occurring primarily in situation or health risk), signalling to the individual that
Psychotherapy, University
Hospital Frankfurt–Goethe adulthood; from the age of 18 years and older). High they might be in danger. This signalling also includes
University, Frankfurt, Germany prevalence, chronicity, and comorbidity led WHO to rank interoceptive stimuli (eg, palpitations or shortness of
(Prof A Reif MD) anxiety disorders as the ninth most health-related cause breath). The main classification schemes, the fifth
Correspondence to: of disability.1 Worldwide, anxiety disorders heavily affect edition of Diagnostic and Statistical Manual of Mental
Prof Brenda W J H Penninx,
patients and society, accounting for 3·3% of the global Disorders (DSM-5) and the 11th edition of International
Department of Psychiatry,
Amsterdam University Medical burden of disease and costing approximately €74 billion Classification of Diseases (ICD-11), define anxiety disor
Center, Vrije Universiteit, for 30 European countries.2 Globally, the use of treatment ders on the basis of similar key symptoms (table 1).
1081 HL Amsterdam, for anxiety disorders is low, which is most problematic Categorical diagnostic criteria are clinically useful, but
Netherlands
in low-income countries but is also an issue in high- boundaries between anxiety disorders and normative
[email protected]
income countries.3 anxiety are often ill-defined. Recognition of distinctions
requires clinical judgement of severity, duration,
Clinical presentation persis
tence, and, importantly, degree of distress and
Fear is a conscious feeling evoked by threat or impending impairment. Symptoms can occur without distress and
danger, whereas anxiety involves anticipation of real or impairment, including cases of specific phobias for
imagined future threat or danger. Both fear and anxiety which people never encounter their feared objects
facilitate survival and are often adaptive. As such, many (eg, snakes). In this instance, medical attention is
generally not needed. Conversely, anxiety symptoms
and panic attacks commonly occur in attenuated forms,
Search strategy and selection criteria supporting dimensional over categorical approaches for
We searched articles in PubMed and Cochrane databases diagnoses. For example, isolated panic attacks do not
using major medical subject headings and title or key words meet the criteria (DSM-5 or ICD-11) for a panic disorder;
for “anxiety disorder”, “separation anxiety”, “selective however, these attacks have been shown to impair func
mutism”, “specific phobia”, “social phobia”, “social anxiety tioning and increase the risk for various other mental
disorder”, “panic disorder”, “agoraphobia”, or “generalized disorders.4 Consequently, panic attacks deserve attention
anxiety disorder” published in English between Jan 1, 2015, as a separate dimension across mental disorders.
and March 1, 2020. From the identified papers, we selectively Symptoms are generally not pathognomonic of
prioritised reviews, meta-analyses, and strong, influential individual anxiety disorders, and anxiety disorder comor
(experimental) studies within maximum reference criteria. bidity is substantial: 48–68% of adults with one anxiety
We focused on the most recent papers unless evidence was disorder fulfil the criteria for another concurrent anxiety
sparse or if older papers were particularly important. disorder.5 Comorbidity is higher in clinical settings
than in community settings because individuals with
Selective mutism Separation anxiety Specific phobia Social anxiety disorder Agoraphobia Panic disorder Generalised anxiety
disorder
Core emotions Consistent failure to Unrealistic, persistent fear Marked, excessive, Marked, excessive, and Marked, excessive, Recurrent, unexpected Marked,
or cognitions speak in situations or anxiety about and unreasonable fear unreasonable fear or and concerning fear of panic attacks with uncontrollable, and
for which there is an separation from, or loss or anxiety of anxiety of scrutiny or leaving home, sustained mental anxious worry and
expectation to of, attachment figure, circumscribed objects negative judgement by entering closed or (eg, fear, fear of losing fears about everyday
speak, despite or adverse events or situations other people open public places, control, or feeling of events and problems
language occurring to them (eg, animals, natural crowds, or alienation)
competence forces, blood transportation manifestations
injection, or places)
Physical No physical Nightmares and No physical Blushing, fear of No physical Multiple symptoms Restlessness,
symptoms symptoms symptoms of distress symptoms vomiting, urgency or symptoms (eg, palpitations, fatigue, irritability,
fear of micturition or dyspnoea, diaphoresis, difficulty
defaecation chest pain, dizziness, concentrating,
paraesthesia, or nausea) muscle tension,
sleep disturbance,
or autonomic
arousal
Behaviour Disturbance Reluctance to leave Avoidance of Avoidance of social Avoidance of fear- Changed behaviour in Disturbance impairs
interferes with attachment figure; circumscribed objects interactions and inducing situations; maladaptive ways social, school, work,
(educational) disturbance impairs or situations; situations; disturbance disturbance impairs related to the attacks; or other functioning
achievement or social, school, or other disturbance impairs impairs social, school, social, school, work, disturbance impairs
social functioning social, school, work, work, or other or other functioning social, school, work or
communication or other functioning functioning other functioning
Required >1 month (beyond >1 month (childhood; >6 months >6 months >6 months >1 month >6 months
symptom first school month) 4–18 years); >6 months
duration (adulthood; 18 years or
older)
Median age of Childhood Childhood Childhood Early adolescence Late adolescence Adulthood Adulthood
onset (<5 years) ( around 6 years) (around 8 years) (around 13 years) (around 20 years) (around 25 years) (around 30 years)
Characteristics and features for anxiety disorders were based on criteria from the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) and International Classification of Diseases (11th edition).
concomitant disorders are more likely to seek treatment. Detection and diagnostic methods
Also, longitudinal diagnostic instability within anxiety Because anxiety disorders are underdiagnosed in all care
disorders is high,6 showing frequent sequential comor settings,3 clinicians should monitor their occurrence.
bidity as well as possible shared causes. Monitoring is particularly important because patients
Anxiety disorders, which are the most common type of who have anxiety disorders often present symptoms
mental disorders in children, represent the earliest of all other than clear anxiety symptoms: for instance, patients
forms of mental illness. Mostly due to separation anxiety, who have panic disorder could present in general care
a specific phobia, or social anxiety disorder, the onset of settings or emergency care settings with presumed
any anxiety disorder is usually in childhood, and thus cardiac or respiratory problems. Given that patients who
considerably earlier than, for example, depressive or have anxiety disorders are mostly seen in primary care,
substance use disorders. Generalised anxiety disorder, clinicians should be aware of these conditions to initiate
agoraphobia, and panic disorder exhibit more age-of- proper treatment or refer to a specialist, if needed.
onset heterogeneity and sometimes present later in life. Because no blood, genetic, or imaging biomarkers exist,
Clarification of anxiety-associated cognitions and diagnosis rests on mental-state history and examinations,
behaviours could show prevailing diagnoses. Avoidance which should therefore be sufficiently monitored by
of social interaction could suggest separation anxiety every primary care practitioner. Validated, structured, or
(if the predominant fear is for losing attachment; semi-structured clinical interviews, such as the DSM-5-
figure 1), panic disorder (if fear is for panic attacks), based or ICD-11-based composite international diagnostic
social anxiety disorder (if fear is for scrutiny by others), interview9 or structured clinical interview for DSM
or agoraphobia (if fear is for entrapment). Fulfilling disorders,10 can assist in correct diagnostics. In children,
multiple anxiety disorder diagnoses could partly reflect interviews such as the Kiddie-SADS11 require additional
artefacts of classi fication systems, but it also holds assessment of parents or caregivers. To determine the
prognostic importance because people with multiple severity of anxiety disorders and monitor treatment,
disorders have higher severity, disability, and a poorer continuous clinician-rated scales include, for example,
disease course compared with people who have a single the Hamilton Anxiety Scale.12 Validated self-report scales
anxiety disorder.7,8 A full clinical assessment is paramount exist for relevant dimensional anxiety disorder aspects:
as it guides treatment selection. examples include the Beck Anxiety Inventory for panic
Table 2: Mental and somatic disorders that are frequently comorbid or difficult to distinguish in anxiety disorder
between 20% and 30%.24,25 This finding suggests that diagnostic criteria, or differences in symptom reporting
one out of three to five children and adolescents have is unclear.35 However, stable sociodemographic correlates
an anxiety disorder at some point in their childhood, exist across nations. Importantly, anxiety disorders are
although not always severe or requiring medical attention. 1·3–2·4 times more prevalent in women than in
In adulthood, 10%–14% of the population fulfil the DSM men,26–31,33 which is accentuated during development and
criteria for anxiety disorder within a year (table 3), most evident after adolescence. Anxiety disorders are also
commonly specific phobia, followed by social anxiety more common in people with unmarried status, low edu
disorder and panic disorder or agoraphobia. The 1-year cation, low income, and those who are unemployed.26–31
prevalence of anxiety disorders is highest in people aged Epidemiological studies show a relatively high ratio
between 18 years and 25 years. The few methodologically of 1 year to lifetime prevalence for anxiety disorders,
sound studies of time trends show no evidence of indicative of a chronic recurrent nature. Prospective
increased anxiety prevalence over the past two decades.32,34 studies,7,19,36 show that patients who have anxiety disorders
However, awareness, seeking of, and provision of could have symptoms for years. Among patients with
treatment has increased,32,34 possibly explaining views of only one anxiety disorder, 2 year remission rates were
the growing effect of anxiety disorders. around 70% for panic disorder without agoraphobia and
In large-scale World Mental Health Surveys done in generalised anxiety disorder, decreasing to 50–55% for
27 countries, anxiety disorder prevalence was highest in social anxiety disorder and panic disorder with
high-income countries.26–29 Whether this finding reflects agoraphobia and 43% for those with multiple anxiety
true regional or cultural differences, problems with disorders.7 A previous study showed that symptoms of
GSMS of children TRAILS of adolescents WMH Surveys of adults (≥18 years; Meta-analysis of adults
followed up (19 years; n=1584)25* n=around 150 000)26–31*† (≥18 years)32‡
through to early
adulthood,
cumulatively over
3 waves (26 years;
n=1420)24
1 year Cumulative 1 year Lifetime Prevalence ratio 1 year Prevalence ratio
of female : male of female : male
Selective mutism ··§ ··§ ··§ ··§ ··§ ·· ··§ ··
Separation anxiety 5·0 0·3 3·1 1·0 4·8 1·4 ·· ··
Specific phobia 2·2 9·0 11·5 5·5 7·4 2·0 6·4 2·4
Social anxiety disorder 4·2 7·5 12·4 2·4 4·0 1·3 2·3 2·1
Agoraphobia 6·1 0·7 1·0 1·0 1·5 1·9 2·0 3·1
Panic disorder 4·8 1·3 1·6 1·0 1·7 2·0 1·8 1·8
Generalised anxiety disorder 9·7 1·8 2·9 1·8 3·7 1·8 1·7 2·1
All anxiety disorders 27·0 18·4 28·0 9·8 ·· ·· 14·0 2·1
··=not examined or reported. *Diagnostic and Statistical Manual of Mental Disorders (fifth edition) Composite International Diagnostic Interview. †From 25 countries.
‡Including 12–18 European studies. §Expected prevalence is <1·0%.
Table 3: Prevalence estimates of anxiety disorder in large-scale studies across age groups
anxiety and avoidance improved in only 309 (44%) aggregation of anxiety disorders suggests that thorough
of 703 patients over 6 years.36 recording of family history during the diagnostic process
Beyond the adverse mental health effects, anxiety is required.
disorders can predict unstable relationships, poorer Until 2010, molecular genetic research has focused
functioning, and higher work absenteeism than in on candidate genes, especially genes relevant in mono
people who do not have these disorders,37,38 with major aminergic neurotransmission or stress axis function.
economic costs and effects on somatic health. Risk of However, a meta-analysis of candidate genes43 only showed
death has been shown to be increased by 1·4 times by an association of panic disorder with TMEM132D gene
natural causes and increased by 2·5 times by unnatural variants and, in subsamples, with HTR2A, NPSR1, and
causes.39 Anxiety has consistently been linked with an MAOA genes.
increased risk of subsequent cardiovascular disease The advent of low-cost genotyping has shifted research
(hazard ratio 1·5),40 with emerging evidence of increased towards genome-wide association studies. The first and
onset risk of other somatic conditions, including stroke, underpowered genome-wide association studies yielded
diabetes, arthritis, and lung disease than in the general none or only few genome-wide significant loci.44–47 When
population.41 Suggested mechanisms of higher comorbid anxiety was examined as a dimension with the use of the
anxiety in persons with somatic illnesses comprise Generalised Anxiety Disorder 2-item scale in 2 million
unhealthy lifestyles, low treatment adherence, and dys people,48 only five genome-wide significant loci were
regulations of psychobiological stress systems. Therefore, identified. Another genome-wide association study49
attention to somatic health should be optimally integrated used a dimensional agoraphobic symptom score and
early on in the treatment of anxiety disorders. related the top hit, in the gene encoding the potentially
druggable GLRB, to panic disorder and intermediate
Pathophysiology phenotypes. Few studies have examined copy number
Genetics variants (ie, larger parts of the genome that are duplicated
Heritability of anxiety disorders can vary, but heritability or deleted). A recent study in children50 suggested that the
estimates converge to rates of between around 35% for presence of copy number variants associated with a high
generalised anxiety disorder and around 50% for social risk for neurodevelopmental disorders increases the risk
anxiety disorder, panic disorder, and agoraphobia.42 The of anxiety disorders by three times. Overall, no converging
mode of inheritance is complex, with many genetic pathways can yet be derived from these initial genome-
variants of small effect interacting with, or adding to, wide association studies. However, genome-wide asso
other (presumably non-shared environmental) risk ciation studies showed a high genetic correlation (rG>0·6)
factors. The genetic basis of anxiety disorders overlaps among people with anxiety, depression, and neuroti
not only within the different disorders but also with the cism,44–46,51 which suggests shared genetic risks and
non-pathological anxiety dimension, suggesting at least a supports the existence of a general genetic risk factor for
partial continuum from normal to pathological anxiety. mental disorders (p factor) that could explain the high
However, the substantial heritability and thus familial comorbidity between most mental disorders.52
Epigenetic mechanisms involve modification of DNA functional MRI studies connect anxiety-related pertur
and chromatin regulating gene expression, which might bations at psychological and neurophysiological levels,
mediate gene–environment interactions and could be with effect sizes of typically 0·50–1·00.72 Treatment
modified by intervention. The inaccessibility of neuronal trials have already extended such translational work
cells poses methodological problems in human studies. in ways that are relevant to clinicians by targeting
Hence, data examining peripheral biomarkers require attention with the goal of reducing the risk and expression
validation via model systems. Hypothesis-driven studies of anxiety disorders.73 Other functional MRI studies
suggest differential methylation of genes like MAOA,53 have isolated responding on threat-learning, extinction,
CRHR1,54 and OXTR55 to be associated with panic and uncontrollable-stress frameworks,57,62,63,65 for which
disorder, social anxiety disorder, and treatment response. anxiety disorder-related hyper-responding was shown to
However, epigenome-wide screenings have also not yet manifest in temporal and prefrontal cortex regions, with
included large enough samples to allow definitive relatively large effects.
conclusions. Taken together, epigenetic and genetic Decision making research finds a robust anxiety
testing cannot yet be recommended for clinical practice; disorder correlate on tasks for which patients make
rather, respective studies might provide mechanistic errors. Such errors, particularly when they are highly
insights and hence avenues for new treatments. salient, evoke a midline encephalography response called
the error-related negativity, which is larger in individuals
Basic neuroscience with anxiety disorders than is in individuals who do not
Basic neuroscience informs attempts to improve have anxiety disorders (Cohen’s d 0·20–0·60).74 Increased
treatment and outcome prediction in people with anxiety error-related negativity could reflect alterations in
disorders. Relative to many mental illnesses, neuro decision making, although people with anxiety disorders
science research regarding anxiety appears more show few other consistent signs of altered decision
clinically relevant because there is strong cross-species making. Increased error-related negativity could also be
conservation in the mammalian responses to danger and viewed as a form of threat hypersensitivity, evoked by the
the associated brain circuitry (figure 1).56–62 This research potential adverse consequences of error commission.
suggests that perturbed threat responding in anxiety To study immediate threat responses, other research
disorders involves dysfunction in the circuitry that has examined behavioural, physiological, or psychological
supports core psychological processes, such as attention, responses to danger. Specifically, patients with anxiety
emotion, learning, and memory.59 disorders have been shown to manifest heightened sensi
Neuroscience research examines how brain circuitry tivity to threats, including attention bias to threat.59,72,75,76
supports learning about threats.56,59,61–63 This learning Such hypersensitivity can manifest in reaction-time,
includes forms of conditioning, extinction, and recon ocular, and multiple psychophysiological measures.59
solidation, a memory updating mechanism.64 By defining Other research has focused on prolonged defensive
plasticity-related factors underlying learning, this research stress-system responding. When people are exposed
has already identified promising novel therapies to treat to stressors, such as public speaking, scary pictures, or
anxiety disorders.56,61 Moreover, other research defines painful stimulation, studies generally report increased
molecular processes, through which genetic risk might stress responses in people with anxiety disorders versus
manifest, and environmentally sensitive processes (such controls across many measures.63,70–72,77 These measures
as hippocampal neurogenesis),61 through which stress include peripheral autonomic, neurochemical, and hor
might increase the risk for anxiety disorders. monal measures, as well as startle response, for which
relevant circuitry has been isolated in basic research.59
Translational research For some measures, including blood inflammatory
Many brain imaging studies have examined the structure indicators, differences between persons with and without
of regions that basic neuroscience implicates in threat anxiety disorders occur even without laboratory stress
responding, showing structural alterations in anxiety tests, suggesting chronically increased responsivity is
disorders within medial temporal, prefrontal cortex, present in normal life.78,79 For peripheral measures, rarely
and cingulate regions.65,66 Because small effect sizes are do effect sizes exceed a Cohen’s d of 0·50, indicating
expected on the basis of data in other mental disorders that these are not useful biomarkers that currently guide
(eg, for depressive or obsessive-compulsive disorders; diagnosis.
pooled Cohen’s d of 0·10–0·30),67–69 structural imaging in
anxiety disorders is minimally clinically relevant. Developmental perspectives
More clinically promising findings are arising in Overall, developmental cascades into chronic anxiety
functional MRI studies when, for example, evoking begin with preclinical signs, followed by (childhood)
threat response. With functional MRI, patients who are anxiety symptoms, culminating in persistent anxiety and
anxious have an altered response in temporal and comorbid conditions.
prefrontal brain regions, which has also been shown in Studies in non-human primates and human infants
functional MRI research regarding attention.65,70,71 Such younger than 4 years have detected develop mental risk
markers related to anxiety symptoms.60 Temperaments in improving anxiety symptoms (stan dardised mean
linked to anxiety involve heightened emotional sensitivity, difference 0·31);85 however, it is unclear whether this
as well as defensive responding to threat exposure.60 Strong improvement translates into reduced anxiety disorder
findings exist for the temperament of behavioural inhi onset. Behavioural lifestyle interventions (eg, stimulating
bition, expressed as reduced movement and vocalisation exercise86 or sleep hygiene87) have shown efficacy in
in the presence of novelty.73 depression prevention, but have barely been tested for
Although unique combinations of genes and anxiety. Supplementation of omega-3 fatty acids in
environmental factors can operate selectively at specific five trials showed no effect in preventing anxiety.88
timepoints across development, others might operate In summary, prevention interventions, mainly concern
more consistently at many points throughout develop ing cognitive behavioural therapy (CBT) or educational
ment.73 Environmental factors that influence the risk for interventions, or both, have a small benefit for anxiety
anxiety disorders at multiple timepoints include various prevention (standardised mean difference 0·31) when
stressful life experiences and parenting practices, meta-analysed across the entire life span (29 studies,
including childhood trauma, separation from attachment 10 430 people).89 Future well-designed randomised con
figures, and forms of overprotective parenting that trolled trials (including adequate sample size and active
limit children’s opportunities to encounter frightening comparators) are needed to determine to what extent,
circumstances in ways that facilitate mastery. which components, and under what conditions anxiety
Part of the pathophysiology of anxiety is shared with prevention programmes can be cost-effective, efficacious,
other mental disorders. Heightened stress responsivity and long lasting.
represents a cross-disorder risk that is initially associated
with anxiety in childhood.57,62,65,71,77 Ultimately, research in Clinical management
this area will help clinicians to predict transitions from Globally, anxiety disorders are underdiagnosed and
anxiety disorders to other problems. Other markers, such undertreated.3 Most people who have anxiety disorders
as perturbed memory, reward processing, and executive will present to, and are managed in, primary care.
functioning occur more prominently in conditions However, effective treatments do exist; these treatments
other than anxiety disorders (eg, depressive disorders).57 not only reduce anxiety symptoms but also improve
Conversely, anxiety-specific pathophysiology markers quality of life and functioning. Randomised studies
could include the error-related negativity and certain concerning medication and psychotherapy cannot easily
varieties of attention bias.58,72,74,76 be compared due to methodological reasons, especially
regarding the effect sizes of the respective control
Prevention condition (eg, placebo, sham therapies, or waiting list
Universal, selective, and indicated prevention strategies controls: placebo can also can have an effect on anxiety
for children or young people might prevent the onset reduction90). The most parsimonious current conclusion
of anxiety disorders. A meta-analysis80 of 47 randomised is that medication and psychotherapy produce benefits
controlled trials of prevention in people aged between with similar effect sizes90 when given as a first-line
5 years and 18 years, mainly concerning psychological treatment, such as in primary care. Therefore, potential
strategies, showed reduced risks for internalising side-effects, ecological factors (such as treatment avail
disorder onset with the use of prevention strategies ability), and patient preference should be discussed in a
versus control. However, only nine studies focused shared decision making process between the clinician
on anxiety onset, and effects do not sustain beyond and patient. Psychoeducation needs to be included as
9 months. In university students, psychoeducation, soon as a diagnosis has been made.
relaxation, or cognitive restructuring programmes have
showed moderate symptom reduction (hedges’ g=0·65),81 Psychotherapy
regardless of delivery format or prevention level. By Evidence-based psychotherapies91 (as pharmacotherapies)
contrast, a network meta-analysis82 of 137 studies among are considered first-line treatments for anxiety disorders.
56 620 participants examining school-based interventions These range from low-intensity interventions incor
showed a high risk of bias and no clear evidence that porating self-help approaches (eg, bibliotherapy) to high-
interventions might reduce anxiety. Young offspring intensity therapies with a specialised therapist according
(aged 4–25 years) of parents with anxiety disorders form to disorder severity. Most evidence exists for the use of
a group who are at high risk, with a 78% increased risk of CBT as a treatment for anxiety disorders. However, the
anxiety disorders.83 In this group, a brief family-based evidence base is not as strong for the use of other
psychosocial prevention programme has been reported psychotherapies, such as psychodynamic-based, inter
to reduce the 1 year incidence of anxiety.84 personal-based, or acceptance-based psychotherapies,
In adults, anxiety prevention has been evaluated in a for treating anxiety disorders. CBT is a short-term
few trials of selective or indicated prevention.85–88 eHealth therapy (consisting of eight to 20 sessions) derived
interventions (involving the delivery of psychotherapy from principles of behavioural and cognitive psychology.
through the internet) have been shown to be effective Practical considerations are shown in panel 1. A key CBT
SAD (n=101*) 97
CBT Psychodynamic therapy 0·56 (0·11 to 1·03)
Anxiety (n=20)101 CBT + medication Medication 0·54 (0·25 to 0·82)
Mixed (n=7)95 iCBT CBT 0·06 (–0·25 to 0·37)
Figure 2: Effect sizes of different treatments in reducing anxiety symptoms based on meta-analytic evidence
CBT=cognitive behavioural therapy. GAD=generalised anxiety disorder. iCBT=therapist-assisted internet cognitive behavioural therapy. PD=panic disorder.
SAD=social anxiety disorder. *Based on network meta-analysis; therefore, sample size reflects all studies included, not just for the specific contrast.
although quetiapine exhibited increased discontinuation generalised anxiety disorder, but evidence is insufficient;
rates. Initial disease severity moderates the effect size of these substances should therefore be limited to second-line
drug treatment both in panic disorder and generalised use. An extended release formulation of quetiapine is
anxiety disorder: a meta-analysis113 showed that effect similar to SSRI with regard to response;116 but this drug is
sizes increased from Cohen’s d 0·2 in mild generalised off-label for generalised anxiety disorder and the associated
anxiety disorder to 0·5 in severe generalised anxiety side-effects, such as weight gain and sedation, limit its use.
disorder; similar effects were shown for panic disorder.
These findings call for caution regarding the use of Combination treatment and treatment non-response
medication in patients who are mildly symptomatic. Combination treatments are used by many patients in
Benzodiazepines are anxiolytic and therefore efficacious clinical reality (eg, when there is treatment resistance,
in most anxiety disorders.100,114 However, these drugs only comorbidity, and complicated courses), although research
act acutely, lead to relapse after discontinuation, and are is underdeveloped.102 Meta-analytic evidence101 has shown
associated with dependency. These compounds therefore that combined psychotherapy plus pharma cotherapy
require strict monitoring. A few other drugs are used in the outperforms pharmacotherapy alone in standard settings.
treatment of anxiety disorders. Pregabalin, which blocks However, resistance to first-line treatments poses a major
voltage-gated calcium channels, is licensed for generalised clinical challenge. Generally, a patient should only be
anxiety disorder in many countries and shows a moderate considered resistant to treatment if both pharmacotherapy
effect size of Cohen’s d 0·37 and a favourable safety and psychotherapy are ineffective. A systematic review117
profile,115 although cases of misuse of the drug have been on augmentation strategies in patients with SSRI-resistant
reported. Buspirone and opipramol are prescribed for anxiety disorders could identify only six medication
combining treatments. Particularly, further research of chronic and disabling courses. Such developments call
escalated therapies to treat treatment-resistant anxiety for measurement-based and guided care systems rather
is called for. Given the global prevalence and burden than user-driven service provision. Only a combined
of anxiety disorders, it is surprising that the current effort in which we better prevent, better recognise, and
medication pipeline is rather empty. A 2019 overview130 more effectively treat anxiety disorders can ultimately
has not listed a single compound in the current reduce the burden that anxiety disorders place on our
medication pipeline, although preclinical studies have society.
suggested a wide range of molecular targets beyond Contributors
serotonin and GABA receptors or transporters (eg, This Seminar was jointly written by the authors; all authors contributed
corticotropin-releasing hormone receptors, translocator equally. All authors approved the final version for submission.
protein, or the endocannabinoid system). Also gluta Declaration of interests
matergic compounds hold future promise; small proof- BWJHP has received unrestricted research funding from Jansen Research
and Boehringer Ingelheim (not related to the contents of this Seminar).
of-concept studies of intravenous ketamine showed DSP received research funding from the National Institute of Mental
beneficial results in generalised anxiety disorder and Health Intramural Research Program through project ZIAMH002781.
social anxiety disorder.131,132 The question of how to EAH has received grants from the OAK Foundation, the Lupina
selectively target neuronal subpopulations that build Foundation, and the Swedish Research Council (not related to the
contents of this Seminar). AR has received honoraria for talks or advisory
pathological defensive responses within the fear network boards from Jansen, Servier, Neuroaxpharm, Medice, Shire (Takeda),
will be the focus of novel therapies in coming years. and SAGE (not related to the contents of this Seminar).
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