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Diagnosis and Management of Anxiety Disorders
Diagnosis and Management of Anxiety Disorders
Management of C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Anxiety Disorders
By Peter Giacobbe, MD, MSc, FRCPC; Alastair Flint, MD, FRCPC, FRANZCP
ABSTRACT
PURPOSE OF REVIEW: This article provides a synopsis of the current
understanding of the pathophysiology of anxiety disorders, the biological CITE AS:
and environmental risk factors that contribute to their development and CONTINUUM (MINNEAP MINN)
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKbH4TTImqenVDZHALwmCBBpa+7mQMjM94UJaVx7skfyayP1fP/NlHCT on 08/15/2018
F
ear is a fundamental emotion expressed in all mammals and is necessary the unlabeled/investigational
for survival. Fear refers to the coordinated emotional, behavioral, and use of D-cycloserine,
gabapentin, pregabalin,
biological response invoked by an immediate threat detected in the propranolol, and quetiapine for
environment, allowing organisms to protect themselves through a the treatment of anxiety
“fight, freeze, or flight” response. In contrast, anxiety is a disorders.
future-oriented affective state in which the individual prepares to cope with an © 2018 American Academy
uncertain but possible negative event in the absence of a triggering stimulus. of Neurology.
CONTINUUMJOURNAL.COM 893
Although fear and anxiety are separate constructs, they share common neural
substrates, as demonstrated by neuroimaging studies.1 Anxiety responses can
be adaptive by orienting the individual toward the detection of a possible threat
and coordinating a set of psychological, behavioral, and biological reactions to
prepare a response to it. Although the transient experience of anxiety is a core
component of the human experience, when this process becomes more context
independent, prolonged, excessive, and more difficult to regulate, it can become
a pathologic state.
As a group, anxiety disorders are the most common class of disorders listed in
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
Anxiety disorders are chronic and disabling conditions; they have been estimated
to be the sixth leading cause of disability worldwide, surpassing that associated
with diabetes mellitus, chronic obstructive pulmonary disease, and
osteoarthritis.2 This article provides a synopsis of the current understanding of
the pathophysiology of anxiety disorders, the biological and environmental risk
factors that contribute to their development and maintenance, and a practical
approach to the diagnosis and treatment of anxiety disorders in adults.
CONTINUUMJOURNAL.COM 895
KEY POINTS the brain. Parental factors associated with anxiety disorders in childhood include
overprotectiveness; interparental conflict; perfectionism; and modeling of
● Environmental factors
involving danger or threat,
reactions to fearful, stressful, or unpredictable situations.21
such as abuse or parental Stressful life events may play a role in precipitating emotional disorders, with
loss, increase the risk of stressors involving loss more typically related to the development of depression,
developing an anxiety whereas those signaling danger or threat have been specifically associated with
disorder later in life.
the onset of anxiety disorders,5 perhaps through excessive or maladaptive
● Females are twice as activation of the threat neurocircuitry. The distal environmental risk factor that
likely to manifest anxiety has the most profound effect on the development of a subsequent anxiety
disorders compared to disorder is childhood sexual abuse, which increases the risk of developing an
males. anxiety disorder by over threefold (odds ratio 3.09; 95% confidence interval, 2.43
to 3.94).22 Early parental loss through death or separation is associated with an
increased risk of subsequent anxiety disorders in offspring, with odds ratios of 1.2
for specific phobia and up to 2.4 for generalized anxiety disorder. A synergistic
relationship appears to exist between previous childhood adversity and the
impact of current stressful life events, whereby greater childhood adversity
produces larger effects of stressful life events on current psychopathology,
supportive of a stress-sensitization model.23 Female gender is a known risk factor
for developing an anxiety disorder, with the rate twice as high in females
compared to males, although it is not clear if this is caused by biological factors or
secondary to the higher rates of stressful life events experienced by women. In
summary, it appears likely that both genetic and environmental factors can
contribute to the development of anxiety disorders, mediated by inherited and
acquired patterns of maladaptive processing of emotional stimuli in the brain.
CLINICAL PRESENTATIONS
This article is confined to the DSM-5 anxiety disorders: panic disorder,
agoraphobia, generalized anxiety disorder, social anxiety disorder, specific
phobia, selective mutism, separation anxiety disorder, substance/medication-
induced anxiety disorder, and anxiety disorder due to another medical condition.
For information on obsessive-compulsive disorder, refer to the article
“Obsessive-Compulsive Disorder” by Peggy M. A. Richter, MD, FRCPC, and
Renato T. Ramos, MD,24 and for information on posttraumatic stress disorder,
refer to the article “Assessment and Management of Posttraumatic Stress
Disorder” by Janet Ellis, MBBChir, MD, FRCPC, and Ari Zaretsky, MD,
FRCPC,25 in this issue of Continuum.
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:
Note: The abrupt surge can occur from a calm state or an anxious state.
1 Palpitations, pounding heart, or accelerated heart rate
2 Sweating
3 Trembling or shaking
4 Sensations of shortness of breath or smothering
5 Feelings of choking
6 Chest pain or discomfort
7 Nausea or abdominal distress
8 Feeling dizzy, unsteady, light-headed, or faint
9 Chills or heat sensations
10 Paresthesias (numbness or tingling sensations)
11 Derealization (feelings of unreality) or depersonalization (being detached from oneself )
12 Fear of losing control or “going crazy”
13 Fear of dying
Note: Culture-specific symptoms (eg, tinnitus, neck soreness, headache, uncontrollable
screaming or crying) may be seen. Such symptoms should not count as one of the four
required symptoms.
B At least one of the attacks has been followed by 1 month (or more) of one or both of the
following:
1 Persistent concern or worry about additional panic attacks or their consequences
(eg, losing control, having a heart attack, “going crazy”)
2 A significant maladaptive change in behavior related to the attacks (eg, behaviors designed
to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations)
C The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication) or another medical condition (eg, hyperthyroidism, cardiopulmonary
disorders)
D The disturbance is not better explained by another mental disorder (eg, the panic attacks
do not occur only in response to feared social situations, as in social anxiety disorder;
in response to circumscribed phobic objects or situations, as in specific phobia; in
response to obsessions, as 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)
CONTINUUMJOURNAL.COM 897
COMMENT This patient’s episodes, although resembling panic attacks, were related to
thyroid hormone excess. Late-onset anxiety disorders should prompt a
search for other psychiatric or medical conditions that may be contributing
to, or mimicking, anxiety (eg mood disorders, medical conditions, and the
physiologic effects of substance use or medication). Elderly patients who
present with panic attacks require a medical workup to rule out a
concurrent medical condition. Red flags for a possible medical etiology for
panic attacks in the elderly include an absence of a personal and family
history of panic disorder; the presence of neurologic symptoms during a
panic attack, such as loss of consciousness, loss of bladder or bowel
control, or syncope; and somatic symptoms without the psychological
symptoms of panic.
Agoraphobia
Agoraphobia was previously designated as a subtype classifier of panic disorder,
but DSM-5 divides agoraphobia and panic disorder into separate diagnostic
entities. Agoraphobia is characterized by marked fear or anxiety about actual or
anticipated exposure within public spaces that lasts at least 6 months, with the
symptoms of fear or anxiety occurring most of the time in more than one setting
(TABLE 12-3). As a result, individuals with agoraphobia fear and avoid these
situations because of worry about developing paniclike symptoms or the belief
that escape might be difficult. Importantly, the feared situations should not be
realistically threatening (eg, walking alone in a dangerous part of town). Those
patients who meet criteria for both disorders would be diagnosed with panic
disorder and agoraphobia.
The lifetime prevalence of agoraphobia has been estimated to be 2%.30 The
relationship between panic disorder and agoraphobia changes across the lifespan.
That is, most older persons with agoraphobia do not have a history of panic attacks35
and develop agoraphobia following the onset of a physical illness or after a traumatic
experience, such as a fall.36 The ability of the clinician to make the diagnostic
distinction between panic disorder with comorbid agoraphobia and agoraphobia
alone has important implications for management, as no robust evidence exists
CONTINUUMJOURNAL.COM 899
Escitalopram X
Fluvoxamine XR X
Fluoxetine X
Paroxetine X X X
Paroxetine CR X
Sertraline X X
Serotonin norepinephrine
reuptake inhibitors (SNRIs)
Duloxetine X
Venlafaxine XR X X X
Azapirones
Buspirone X
Benzodiazepines
Alprazolam X
Clonazepam X
A Marked fear or anxiety about two (or more) of the following five situations:
1 Using public transportation (eg, automobiles, buses, trains, ships, planes)
2 Being in open spaces (eg, parking lots, marketplaces, bridges)
3 Being in enclosed places (eg, shops, theaters, cinemas)
4 Standing in line or being in a crowd
5 Being outside of the home alone
B The individual fears or avoids these situations because of thoughts that escape might
be difficult or help might not be available in the event of developing paniclike symptoms
or other incapacitating or embarrassing symptoms (eg, fear of falling in the elderly; fear
of incontinence)
C The agoraphobic situations almost always provoke fear or anxiety
D The agoraphobic situations are actively avoided, require the presence of a companion, or
are endured with intense fear or anxiety
E The fear or anxiety is out of proportion to the actual danger posed by the agoraphobic
situations and to the sociocultural context
F The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more
G The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning
H If another medical condition (eg, inflammatory bowel disease, Parkinson disease) is
present, the fear, anxiety, or avoidance is clearly excessive
I The fear, anxiety, or avoidance is not better explained by the symptoms of another mental
disorder—for example, the symptoms are not confined to specific phobia, situational type;
do not involve only social situations (as in social anxiety disorder); and are not related
exclusively to obsessions (as in obsessive-compulsive disorder), perceived defects or flaws in
physical appearance (as in body dysmorphic disorder), reminders of traumatic events (as in
posttraumatic stress disorder), or fear of separation (as in separation anxiety disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic disorder. If an
individual’s presentation meets criteria for panic disorder and agoraphobia, both diagnoses
should be assigned.
CONTINUUMJOURNAL.COM 901
A Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at
least 6 months, about a number of events or activities (such as work or school performance)
B The individual finds it difficult to control the worry
C The anxiety and worry are associated with three (or more) of the following six symptoms
(with at least some symptoms having been present for more days than not for the past
6 months):
Note: Only one symptom is required in children.
1 Restlessness or feeling keyed up or on edge
2 Being easily fatigued
3 Difficulty concentrating or mind going blank
4 Irritability
5 Muscle tension
6 Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep
D The anxiety, worry, or physical symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas of functioning
E The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication) or another medical condition (eg, hyperthyroidism)
F The disturbance is not better explained by another mental disorder (eg, anxiety or worry
about having panic attacks in panic disorder, negative evaluation in social anxiety disorder
[social phobia], contamination 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 appearance flaws in body
dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of
delusional beliefs in schizophrenia or delusional disorder)
CONTINUUMJOURNAL.COM 903
Specific Phobia
The cross-national lifetime prevalence of specific phobia has been estimated to
be 7.4%.43 Natural environment phobias (eg, fear of bodies of water or heights)
are the most common subtype, followed by situational phobias (eg, flying),
animal phobias (eg, spiders or dogs), and blood-injury phobias (eg, fear of
needles). In contrast to other anxiety disorders, the blood-injury subtype of
specific phobia involves decreased rather than increased sympathetic nervous
system activity, leading to syncope and vasovagal-type reactions.44
Approximately 75% of cases of specific phobia will have their onset within
the first decade of life.45 Having multiple specific phobias is the rule rather
A Marked fear or anxiety related to one or more social situations in which the individual is
exposed to scrutiny by others. Examples include social interactions (eg, having a
conversation, meeting unfamiliar people), being observed (eg, eating or drinking), and
performing in front of others (eg, giving a speech).
Note: In children, the anxiety must occur in peer setting and not just during interactions with
adults.
B The individual fears that he or she will act in a way or show anxiety symptoms that will be
negatively evaluated (ie, will be humiliating or embarrassing; will lead to rejection or
offend others).
C The social situations almost always provoke fear or anxiety.
Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing,
clinging, shrinking, or failing to speak in social situations.
D The social situations are avoided or endured with intense fear or anxiety.
E The fear or anxiety is out of proportion to the actual threat posed by the social situation
and to sociocultural context.
F The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
G The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
H The fear, anxiety, or avoidance is not attributable to the physiologic effects of a substance
(eg, a drug of abuse, a medication) or another medical condition.
I The fear, anxiety, or avoidance is not better explained by the symptoms of another mental
disorder, such as panic disorder, body dysmorphic disorder, or autism spectrum disorder).
J If another medical condition (eg, Parkinson disease, obesity, disfigurement from burns or
injury), is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive.
CONTINUUMJOURNAL.COM 905
Selective Mutism
Selective mutism is characterized by an individual’s failure to speak in certain
social situations, with the presence of normal ability to speak in other settings.
The prevalence rates of selective mutism have been estimated to range from
0.11% to 2.2% in children, with an average age of onset of 2 to 5 years. The most
common presentation is failure to speak in school, resulting in significant
adaptation difficulties in social and academic spheres.47
Identified risk factors for selective mutism include a temperament of
behavioral inhibition, communication delays, bilingualism, immigration, and a
history of parental social anxiety disorder or selective mutism. Although the
majority of children with selective mutism have a complete remission of their
symptoms in adolescence, rates of mood and anxiety disorders are high in
adulthood, with 58% having a psychiatric disorder, most commonly social
anxiety disorder.48
Treatment approaches consist of psychoeducation, cognitive-behavioral
therapy, and graduated exposure to situations requiring verbal communication.
No medications are FDA approved for selective mutism; limited literature exists
for the use of SSRIs.49
CONTINUUMJOURNAL.COM 907
KEY POINTS The GAD-7 is a seven-item questionnaire with total scores ranging from 0 to 21.
A total score in the range of 5 to 9 is consistent with mild anxiety, 10 to 14 with
● Education about the
nature of anxiety disorders,
moderate anxiety, and 15 or more with severe anxiety. For those with mild
avoidance of known anxiety, the treatment recommendation is for psychoeducation, support, and
exacerbating factors, the watchful waiting; if symptoms worsen, cognitive-behavioral therapy may be
promotion of healthy coping added (including Internet- or computer-based cognitive-behavioral therapy).
strategies, and emotional
Cognitive-behavioral therapy, pharmacotherapy, or both are recommended for
support should be provided
to all patients. those with moderate anxiety. Severe or treatment-resistant anxiety symptoms
warrant cognitive-behavioral therapy concurrently with pharmacotherapy.42
● A stepped-care approach
for those with moderate or Treatment Approach for Mild Symptoms
severe anxiety has been
recommended.
Patients and their families should be given education about the nature of anxiety,
including both psychological and physical symptoms; the known clinical course
● The routine of the specific anxiety disorder(s) affecting them; and the treatment options
coadministration of available. Clinical experience suggests that patients greatly benefit from
psychotherapy and
discussions emphasizing the common frequency of anxiety conditions, the
medications has not been
shown to be superior to biological and genetic component of anxiety, and the good recovery rates with
either approach alone. treatment. Patients should also be educated to avoid possible common
exacerbating factors for anxiety, such as excessive use of caffeine or alcohol, and
● Robust data exist to to potentially reduce medications with stimulating properties. Medications and
support cognitive-
behavioral therapy in the
substances with sedating effects, such as alcohol or marijuana, may be commonly
treatment of anxiety used by people to try to alleviate anxiety; however, they can potentially
disorders, whether precipitate panic and anxiety in the withdrawal phase (CASE 12-3). Patients
administered directly by a should be encouraged to get regular aerobic exercise and to practice
therapist or via the Internet.
relaxation techniques.
In patients who present with anxiety disorders, it is essential to assess for COMMENT
the presence of alcohol and substance abuse. Benzodiazepines should be
avoided in patients with a history of substance abuse because of the
potential for dependence and the ability of benzodiazepines to potentiate
the effects of alcohol and opioids, which can increase the likelihood of death
in overdose. In cases where pharmacologic interventions are deemed
necessary, priority should be given to selective serotonin reuptake inhibitors
(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and buspirone,
although it may take weeks to months to see the full effects of these
medications. Pregabalin, a medication that does not bind to benzodiazepine
receptors and has reduced addiction potential, was given to provide more
immediate anxiolysis given this patient’s history of substance abuse.
CONTINUUMJOURNAL.COM 909
CONTINUUMJOURNAL.COM 911
}
Selective serotonin reuptake inhibitors (SSRIs)b
Citalopramc 10 20–40 Daily
c,d
Escitalopram 5 10–20 Daily
Venlafaxine XRd
30
37.5
60–90
75–225
Daily in the morning
Azapirones
Buspironed 10 20–60 Daily Dizziness, nausea, insomnia,
headache
}
Benzodiazepines
Alprazolamd 0.5–1.0 2–6 3 times a day
d Sedation, psychomotor
Clonazepam 0.25–0.50 1–2 Daily or 2 times a day
impairment, dependence,
Diazepam 2.5–5.0 10–40 Daily tolerance
Lorazepam 0.5–1.0 1–4 2 times a day
Other
Gabapentin 100–200 100–1800 2 or 3 times a day Sedation
a
Lower dosages are recommended for the elderly.
b
Evidence exists for the efficacy of SSRIs and SNRIs beyond those with a US Food and Drug Administration (FDA) indication for an anxiety disorder,
suggesting that this may be a class effect rather than restricted to certain compounds.
c
A warning exists of increased risk of the QT prolongation at doses of citalopram greater than 40 mg (greater than 20 mg in those older than 60 years
of age) and escitalopram greater than 20 mg. In those age 65 years and older, the maximum recommended dose of citalopram is 20 mg/d63 and
the maximum recommended dose of escitalopram is 10 mg/d64 (Health Canada). The FDA recommends a maximum dose of 20 mg/d for citalopram in
those older than age 60.65 For escitalopram, the maximum recommended dose is 10 mg/d in the elderly.66
d
FDA indication for an anxiety disorder.
Escitalopram 0–9% 0–9% 0–9% 0–9% 0–9% 0–9% 10–29% 0–9% 10–29%
Fluvoxamine 10–29% 0–9% 10–29% 0–9% >30% 10–29% >30% >30% >30%
Fluoxetine 0–9% 0–9% 10–29% 0–9% 0–9% 10–29% 10–29% 10–29% 10–29%
Paroxetine 10–29% 10–29% 10–29% 0–9% 10–29% 10–29% 10–29% 10–29% >30%
Sertraline 0–9% 10–29% 10–29% 10–29% >30% 10–29% >30% 10–29% >30%
Duloxetine 10–29% 0–9% 10–29% 0–9% 0–9% 10–29% >30% 0–9% 10–29%
Venlafaxine 10–29% 0–9% 10–29% 0–9% 10–29% 10–29% >30% 10–29% 10–29%
a
Based on unadjusted rates from product monographs.
CONTINUUMJOURNAL.COM 913
CONCLUSION
Anxiety is often a transient response to perceived threats, which coordinates a
set of psychological, behavioral, and biological reactions to prepare the individual
CONTINUUMJOURNAL.COM 915
USEFUL WEBSITES
ANXIETY AND DEPRESSION ASSOCIATION OF AMERICA NATIONAL INSTITUTE OF MENTAL HEALTH
The Anxiety and Depression Association of America The National Institute of Mental Health webpage on
website provides resources for understanding anxiety disorders provides educational resources,
depression, anxiety, and stress; information about including signs and symptoms, risk factors, and
suicide prevention; and links for treatment and treatments and therapies. It also includes
support. information on how to join a clinical trial for anxiety
adaa.org disorders.
nimh.nih.gov/health/topics/anxiety-disorders/
MOODGYM index.shtml
MoodGym is a free online cognitive-behavioral
therapy resource.
moodgym.com.au
REFERENCES
1 Williams LM. Defining biotypes for depression 4 Huang H, Thompson W, Paulus MP.
and anxiety based on large-scale circuit Computational dysfunctions in anxiety: failure to
dysfunction: a theoretical review of the evidence differentiate signal from noise. Biol Psychiatry
and future directions for clinical translation. 2017;82(6):440–446. doi:10.1016/j.biopsych.
Depress Anxiety 2017;34(1):9–24. doi:10.1002/ 2017.07.007.
da.22556.
5 Craske MG, Stein MB. Anxiety. Lancet 2016;
2 Baxter AJ, Vos T, Scott KM, et al. The global 388(10063):3048–3059. doi:10.1016/S0140–6736
burden of anxiety disorders in 2010. Psychol (16)30381–6.
Med 2014;44(11):2363–2374. doi:10.1017/
6 Robinson OJ, Letkiewicz AM, Overstreet C, et al.
S0033291713003243.
The effect of induced anxiety on cognition:
3 Browning M, Behrens TE, Jocham G, et al. Anxious threat of shock enhances aversive processing in
individuals have difficulty learning the causal healthy individuals. Cogn Affect Behav Neurosci
statistics of aversive environments. Nat Neurosci 2011;11(2):217–227. doi:10.3758/s13415–011–0030–5.
2015;18(4):590–596. doi:10.1038/nn.3961.
CONTINUUMJOURNAL.COM 917
32 Imai H, Tajika A, Chen P, et al. Psychological 45 Beesdo K, Pine DS, Lieb R, Wittchen HU.
therapies versus pharmacological interventions Incidence and risk patterns of anxiety and
for panic disorder with or without agoraphobia depressive disorders and categorization of
in adults. Cochrane Database Syst Rev 2016;10: generalized anxiety disorder. Arch Gen
CD011170. doi:10.1002/14651858.CD011170.pub2. Psychiatry 2010;67(1):47–57. doi:10.1001/
archgenpsychiatry.2009.177.
33 Katzman MA, Bleau P, Blier P, et al. Canadian
clinical practice guidelines for the management 46 Hannigan LJ, Walaker N, Waszczuk MA, et al.
of anxiety, posttraumatic stress and obsessive- Aetiological influences on stability and change
compulsive disorders. BMC Psychiatry 2014;(14 in emotional and behavioural problems
suppl 1):S1. doi:10.1186/1471–244X-14-S1-S1. across development: a systematic review.
Psychopathol Rev 2017;4(1):52–108. doi:10.5127/
34 Nay W, Brown R, Roberson-Nay R. Longitudinal
pr.038315.
course of panic disorder with and without
agoraphobia using the National Epidemiologic 47 Hua A, Major N. Selective mutism. Curr Opin
Survey on Alcohol and Related Conditions Pediatr 2016;28(1):114–120. doi:10.1097/
(NESARC). Psychiatry Res 2013;208(1):54–61. MOP.0000000000000300.
doi:10.1016/j.psychres.2013.03.006.
48 Steinhausen HC, Wachter M, Laimböck K,
35 McCabe L, Cairney J, Veldhuizen S, et al. Metzke CW. A long-term outcome study of
Prevalence and correlates of agoraphobia in selective mutism in childhood. J Child Psychol
older adults. Am J Geriatr Psychiatry 2006;14(6): Psychiatry 2006;47(7):751–756. doi:10.1111/
515–522. doi:10.1097/01. j.1469–7610.2005.01560.x.
JGP.0000203177.54242.14.
49 Manassis K, Oerbeck B, Overgaard KR. The use
36 Giacobbe P, Flint AJ. Panic disorder in the of medication in selective mutism: a systematic
elderly. Aging Health 2007;3(2):245–255. doi: review. Eur Child Adolesc Psychiatry 2016;25(6):
10.2217/1745509X.3.2.245. 571–578. doi:10.1007/s00787–015–0794–1.
37 Goodwin H, Yiend J, Hirsch CR. Generalized 50 Baldwin DS, Gordon R, Abelli M, Pini S. The
anxiety disorder, worry and attention to threat: separation of adult separation anxiety disorder.
a systematic review. Clin Psychol Rev 2017;54: CNS Spectr 2016;21(4):289–294. doi:10.1017/
107–122. doi:10.1016/j.cpr.2017.03.006. S1092852916000080.
38 Stein MB, Sareen J. Clinical practice. Generalized 51 Silove D, Alonso J, Bromet E, et al. Pediatric-
anxiety disorder. N Engl J Med 2015;373(21): onset and adult-onset separation anxiety
2059–2068. doi:10.1056/NEJMcp1502514. disorder across countries in the World Mental
Health Survey. Am J Psychiatry 2015;172(7):
39 Leichsenring F, Leweke F. Social anxiety
647–656. doi:10.1176/appi.ajp.2015.14091185.
disorder. N Engl J Med 2017;376(23):2255–2264.
doi:10.1056/NEJMcp1614701. 52 Milrod B, Markowitz JC, Gerber AJ, et al.
Childhood separation anxiety and the
40 Steinert C, Hofmann M, Leichsenring F, Kruse J.
pathogenesis and treatment of adult anxiety.
What do we know today about the prospective
Am J Psychiatry 2014;171(1):34–43. doi:10.1176/
long-term course of social anxiety disorder? A
appi.ajp.2013.13060781.
systematic literature review. J Anxiety Disord
2013;27(7):692–702. doi:10.1016/j. 53 Battaglia M. Separation anxiety: at the
janxdis.2013.08.002. neurobiological crossroads of adaptation and
illness. Dialogues Clin Neurosci 2015;17(3):277–285.
41 Spitzer RL, Kroenke K, Williams JB, Löwe B. A
brief measure for assessing generalized anxiety 54 Sobanski T, Wagner G. Functional neuroanatomy
disorder: the GAD-7. Arch Intern Med 2006;166 in panic disorder: status quo of the research.
(10):1092–1097. doi:10.1001/archinte.166.10.1092. World J Psychiatry 2017;7(1):12–33. doi:10.5498/
wjp.v7.i1.12.
42 Stein MB, Craske MG. Treating anxiety in
2017: optimizing care to improve outcomes. 55 Bandelow B, Reitt M, Röver C, et al. Efficacy of
JAMA 2017;318(3):235–236. doi:10.1001/ treatments for anxiety disorders: a meta-
jama.2017.6996. analysis. Int Clin Psychopharmacol 2015;30(4):
183–192. doi:10.1097/YIC.0000000000000078.
43 Wardenaar KJ, Lim CCW, Al-Hamzawi AO, et al.
The cross-national epidemiology of specific 56 Cuijpers P, Gentili C, Banos RM, et al. Relative
phobia in the World Mental Health Surveys. effects of cognitive and behavioral therapies on
Psychol Med 2017;47(10):1744–1760. doi:10.1017/ generalized anxiety disorder, social anxiety
S0033291717000174. disorder and panic disorder: a meta-analysis.
J Anxiety Disord 2016;43:79–89. doi:10.1016/j.
44 Donadio V, Liguori R, Elam M, et al. Arousal
janxdis.2016.09.003.
elicits exaggerated inhibition of sympathetic
nerve activity in phobic syncope patients. Brain 57 Barlow DH, Farchione TJ, Bullis JR, et al. The
2007;130(pt 6):1653–1662. doi:10.1093/brain/ unified protocol for transdiagnostic treatment
awm037. of emotional disorders compared with
diagnosis-specific protocols for anxiety
disorders: a randomized clinical trial. JAMA
Psychiatry 2017;74(9):875–884. doi:10.1001/
jamapsychiatry.2017.2164.
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