Study Points

Anxiety Disorders

Course #76182 -

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Study Points

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  1. Review basic concepts related to anxiety disorders, including safety behaviors/signals and primary features.
  2. Outline the epidemiology of anxiety disorders in the United States.
  3. Describe general risk factors for and comorbidities of anxiety disorders.
  4. Describe risk factors for and the clinical course of specific anxiety disorders.
  5. Discuss the pathogenesis of anxiety disorders in relation to contributing genetic, physiologic, and psychologic factors.
  6. Review the pathophysiology of specific anxiety dis­orders, including social anxiety disorder, agoraphobia, and specific phobia.
  7. Evaluate the clinical and diagnostic criteria for anxiety disorders presented in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).
  8. Analyze key components of screening for anxiety disorders.
  9. List conditions to consider in the differential diagnosis of anxiety disorders.
  10. Describe general treatment considerations for anxiety disorders, including predictors of response or nonresponse to therapy.
  11. Discuss the role of various psychotherapy approaches in the treatment of anxiety disorders.
  12. Outline pharmacotherapy options for the treatment of anxiety disorders.
  13. Recognize clinical issues related to the treatment of anxiety disorders.
  14. Compare and contrast the treatment recommen­dations for specific anxiety disorders.
  15. Analyze the evidence base supporting the efficacy of novel, emerging, and alternative/complementary approaches to the treatment of anxiety disorders.
  1. Safety behaviors and safety signals are most accurately described as

    BACKGROUND

    Safety behaviors are coping tactics by persons with anxiety disorders, especially panic disorder, agoraphobia, and social anxiety disorder, to temporarily diminish feelings of threat and reduce one's anxiety level. Safety behaviors can emerge in response to an external (e.g., situations, persons, activities) or internal (e.g., thoughts, emotions, memories) focus of perceived threat and are anticipatory (avoidant) or consequential (escape) [1].

    Safety signals are the people or objects used by patients with anxiety disorders to diminish distress in situations that elicit anxiety. Safety signals maintain anxiety over time by preventing direct confrontation of feared stimuli in the absence of "safe" objects/people and by maintaining perceptions of risk/harm and coping inability. Patient use of safety signals can interfere with therapy progress, especially exposure therapy, and are considered anti-therapeutic. However, safety behaviors may be helpful early in treatment by making exposure therapy more tolerable and less threatening [1].

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  2. Which of the following statements regarding safety behaviors and safety signals is TRUE?

    BACKGROUND

    Safety signals are the people or objects used by patients with anxiety disorders to diminish distress in situations that elicit anxiety. Safety signals maintain anxiety over time by preventing direct confrontation of feared stimuli in the absence of "safe" objects/people and by maintaining perceptions of risk/harm and coping inability. Patient use of safety signals can interfere with therapy progress, especially exposure therapy, and are considered anti-therapeutic. However, safety behaviors may be helpful early in treatment by making exposure therapy more tolerable and less threatening [1].

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  3. All of the following are classed as anxiety disorders in the DSM-5, EXCEPT:

    BACKGROUND

    The distinguishing features of specific anxiety disorders are summarized in the following section. Related conditions of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD) are included because, although no longer classed as anxiety disorders by the 2013 Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), they are often included in research that pre-dates 2013 and can co-occur with anxiety disorders [2]. Situations or objects that evoke intense anxiety in patients with agoraphobia, social anxiety disorder, or specific phobia are either avoided or endured with significant personal distress.

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  4. Generalized anxiety disorder (GAD) is characterized by excessive and inappropriate worrying that is persistent (lasting more than a few months) and not restricted to particular circumstances.

    BACKGROUND

    Generalized anxiety disorder (GAD) is characterized by excessive and inappropriate worrying that is persistent (lasting more than a few months) and not restricted to particular circumstances [3]. Patients with GAD have physical anxiety symptoms and key psychologic symptoms (i.e., restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and disturbed sleep). GAD is often comorbid with major depression, panic disorder, phobic anxiety disorders, health anxiety, and OCD [3].

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  5. Around two-thirds of patients with panic disorder develop agoraphobia.

    BACKGROUND

    Around two-thirds of patients with panic disorder develop agoraphobia, defined as fear of having panic attacks in places or situations from which escape might be difficult or where help might not be available [3]. These places or situations can include crowds, outside of the home, or using public transport [2].

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  6. SAD is characterized by fear or anxiety concerning separation from those to whom an individual is attached.

    BACKGROUND

    Social anxiety disorder (SAD) is characterized by a marked, persistent, and unreasonable fear of being negatively evaluated by others [3]. It is associated with physical and psychologic anxiety symptoms.

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  7. Annually in the United States, the number of adults experiencing DSM-5 anxiety disorders plus PTSD and obsessive-compulsive disorder (OCD) is

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Each year in the United States, anxiety disorders (DSM-5 plus PTSD and OCD) impact approximately 42 million adults, or 19% of the population [4,5]. The pattern of sex distribution is consistent among anxiety disorders, and the overall female-to-male ratio is approximately 2:1 across all age ranges [6].

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  8. Which of the following anxiety disorders has the highest lifetime prevalence?

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    COMPARISON OF PREVALENCE, MORBID RISK, AND RATIO OF LIFETIME PREVALENCE TO MORBID RISK FOR ANXIETY DISORDERS

    Anxiety Disorder12-monthLifetimeLifetime Morbid RiskLifetime/Lifetime Morbid Risk
    Generalized anxiety disorder2.0%4.3%9.0%0.5
    Panic disorder2.4%3.8%6.8%0.5
    Agoraphobia1.7%2.5%3.7%0.7
    Social anxiety disorder7.4%10.7%13.0%0.8
    Specific phobia12.1%15.6%18.4%0.8
    Separation anxiety disorder1.2%6.7%8.7%0.8
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  9. Which of the following anxiety disorders has a later age of onset?

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Anxiety disorders with earlier median age of onset are phobias and separation anxiety disorder (15 to 17 years of age), and those with latest age of onset are panic disorder and generalized anxiety disorder (23 to 30 years of age). Lifetime morbid risk is considerably higher than lifetime prevalence for most anxiety disorders, with magnitude of difference much higher for disorders with later than earlier age of onset. Also, the ratio of 12-month to lifetime prevalence roughly reflects persistence, but varies meaningfully in ways consistent with differential persistence of these disorders [7].

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  10. Which of the following demographic factors is associated with a higher risk of anxiety disorder diagnosis?

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    The odds for a lifetime diagnosis of any anxiety disorder were calculated, and the same pattern was found for past 12 month diagnosis [8]. These odds are organized according to sex, socioeconomic status, education level, and age. Overall, the risk of developing an anxiety disorder is greater for women/girls than men/boys.

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  11. Behavioral inhibition is an identifiable early childhood predictor of later anxiety disorders.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Behavioral inhibition is defined as the tendency for timid and shy responses to novel situations, and it is highly associated with temperament factors of neuroticism and introversion. Anxiety disorders are associated with behavioral inhibition in childhood, and behavioral inhibition is an identifiable early childhood predictor of later anxiety disorders. Introversion and behavioral inhibition are also strongly linked to later development and severity of situational avoidance, which is a core feature and risk factor in agoraphobia and SAD [9].

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  12. The greatest concentration of anxiety disorders occurs in older adults (older than 60 years of age).

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Anxiety disorders in aggregate show a U-shaped age of onset—higher in childhood and young adulthood and lower in adolescence. The greatest concentration occurs during transition to early adulthood. Unlike biologically driven pubertal transitions, adulthood transitions involve distinct psychosocial events (e.g., independent living, full-time employment), and this represents a key period for understanding the development of adult anxiety disorders such as panic disorder and agoraphobia [10].

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  13. Anxiety disorders are highly prevalent comorbidities in all of the following conditions, EXCEPT:

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Anxiety symptoms often co-occur with other psychologic symptoms. Depressive symptoms are highly prevalent with more severe anxiety symptoms, with anxiety and depressive symptom severity strongly correlated. Patients with anxiety disorder have high comorbidity rates of major depressive disorder (almost 50%), schizophrenia, substance use disorders, and physical illness [3,11]. Overlapping symptoms of anxiety and depression, such as sleep disturbance, fatigue, and difficulty concentrating, make differentiation challenging. Depressive disorders are sometimes termed "anxious-misery" when high levels of sadness and anhedonia are present [2].

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  14. The primary predictors of late-onset GAD include female sex, recent adverse life events, and chronic physical or mental health disorders.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Late-onset GAD (on or after 65 years of age) is very uncommon. The primary predictors include female sex, recent adverse life events, and chronic physical (e.g., respiratory and cardiac disorders, dyslipidemia, cognitive impairment) or mental health (e.g., depression, phobia, past GAD) disorders. Other risk factors include poverty, parental loss/separation or low emotional support during childhood, and history of parental mental health problems. Late-onset GAD is described as a multifactorial, stress-related affective disorder resulting from proximal and distal risk factors of which some are potentially modifiable by healthcare intervention [14].

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  15. What is the annual incidence of panic disorder in the United States?

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    In the United States, 4% to 28% of the population experience panic attacks at some time during their life. The 2.4% annual incidence of panic disorder in the United States is one of the highest prevalence rates worldwide [7,18].

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  16. Longitudinal studies show high remission rates (83% to 100%) over time in panic disorder or agoraphobia.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Longitudinal studies show low remission rates (0% to 23%) over time in panic disorder or agoraphobia, and subjects with panic disorder with agoraphobia or agoraphobia with panic attacks at baseline were more likely to develop agoraphobia, panic attacks, and other anxiety disorders and experience greater severity (e.g., impairment, disability, treatment-seeking, comorbidity) than subjects with panic disorder without agoraphobia or agoraphobia without panic attacks at baseline [35].

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  17. SAD can develop at any time during a lifespan, but the average age of onset is during late childhood and adolescence.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    SAD can develop at any time during a lifespan, but the average age of onset is during late childhood and adolescence. The prevalence of SAD in pre-adolescence is 3.5%, with rates increasing to about 14% during adolescence [41]. The incidence is as high as 7% in primary care settings [19]. Gender distribution is generally equal during pre-adolescence and becomes increasingly more common in girls/women through adolescence and adulthood. An estimated 70% to 80% of individuals with SAD have comorbid anxiety, mood, or substance use disorders. There are cultural variants in Asian and Eastern cultures that involve fears of offending others or making others uncomfortable [2].

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  18. Learned escape and avoidance behaviors prevent anxiety, promote skill development, and can lead to improvements in functional impairment and disability over time.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Multiple social cues can develop the capacity to elicit anxiety-related symptoms. Learned escape and avoidance behaviors maintain anxiety, interfere with skill development, and can lead to functional impairment and disability over time. Similarly, safety behaviors, such as only entering social situations with a trusted companion, averting eye contact, and staying on the periphery of social gatherings, may maintain anxiety-related impairments. Selective attention to social cues of negative evaluation and internal cues supporting danger perception may develop [49,50].

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  19. Primary prevention by recognizing excessive childhood fearfulness and behavioral inhibition, and appropriate intervention, may prevent future

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    Childhood presence of fearfulness and behavioral inhibition can lead to chronic, disabling SAD. Early recognition of childhood impairments and evidence-based treatment intervention may offset the SAD trajectory of persisting into and through adulthood. Educational-behavioral interventions involving older children/adolescents, parents, school staff, and healthcare providers have been found to reduce the development of social anxiety [51,52,53].

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  20. Boys/men show higher overall prevalence of SEPAD than girls/women and substantially higher rates of childhood-onset SEPAD persisting into adulthood.

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    The lifetime prevalence of adult SEPAD is 6.6% in the general population, 12% to 40% in psychiatric clinic settings, and more than 75% among those seeking treatment at anxiety disorder clinics [61]. In adults with lifetime SEPAD, 22.5% have childhood age of onset that persisted into adulthood, while 77.5% had adult onset. Girls/women show higher overall prevalence than boys/men and substantially higher rates of childhood-onset SEPAD persisting into adulthood [62]. SEPAD and panic disorder are highly comorbid in clinical settings. Among adult patients with panic disorder, 53.2% were diagnosed with SEPAD. Patients with panic disorder and SEPAD (versus no SEPAD) were more commonly female and younger and showed higher rates of childhood SEPAD and greater lifetime prevalence of mood disorder spectrum symptoms [63].

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  21. Children with separation anxiety disorder are more likely to develop which of the following in adulthood?

    OVERALL PREVALENCE, RISK FACTORS, AND CLINICAL COURSE

    In one study, children with SEPAD were 3.5 times more likely to later develop panic disorder and more than twice as likely to develop any anxiety disorder but did not significantly differ in later development of depression or substance use disorder. These findings were considered supportive of a developmental psychopathology model of anxiety disorders [65].

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  22. Fear and anxiety are thought to involve two major brain circuits: the limbic system and the prefrontal cortex.

    ETIOLOGY AND PATHOPHYSIOLOGY

    Fear and anxiety are thought to involve two major brain circuits: the limbic system and the prefrontal cortex. In the limbic system, which consists of the amygdala, hippocampus, central nucleus of the amygdala, insular cortex, and cingulate cortex, emotion-processing brain structures generate primitive innate responses to simple, overtly threatening stimuli. Functions of limbic structures include processing emotionally important external stimuli and initiating behavioral responses; mediating expressions of fear, aggression, and defensive behavior; and forming and retrieving emotional and fear-related memories [66,67]. The prefrontal cortex, comprised of the orbitofrontal cortex and the prefrontal, ventromedial, and dorsomedial prefrontal cortex, dampens emotional responses to anxiety-inducing stimuli. The prefrontal cortex functions to regulate impulses, emotions, and behavior via inhibitory "top-down" control of emotional-processing structures; this works to control impulses and regulate mood [66,67].

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  23. In several anxiety disorders, an underlying pathophysiology is thought to involve

    ETIOLOGY AND PATHOPHYSIOLOGY

    Altered limbic and prefrontal cortex functioning characterize anxiety disorders, with amygdala hyper-responsivity to threatening stimuli and impaired ventromedial prefrontal contex inhibitory control over limbic-generated, anxiety-inducing signals, associated with aberrant communication and functional connectivity between the amygdala and the prefrontal cortex [67].

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  24. Previous childhood or adult trauma is considered a predisposing/contributing factor to panic disorder and SEPAD as well as major depressive disorder and PTSD that may be primary or comorbid with other anxiety disorders.

    ETIOLOGY AND PATHOPHYSIOLOGY

    Significant early-life stress (e.g., maternal deprivation) may degrade prefrontal cortex functional connectivity with subcortical panic-generating circuits, elevating risks of anxiety disorders and other psychopathology. Many significant early-life stress events (e.g., child abuse, neglect, parental loss from death or abandonment) are receiving heightened attention as contributing factors to anxiety disorders and trauma pathology, as in PTSD. Previous childhood or adult trauma is considered a predisposing/contributing factor to panic disorder and SEPAD as well as major depressive disorder and PTSD that may be primary or comorbid with other anxiety disorders [69]. Aversive experiences can lead to complex behavioral adaptations, including increased levels of anxiety and fear generalization.

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  25. The underlying neurotransmitter abnormality in many anxiety disorders involves only

    ETIOLOGY AND PATHOPHYSIOLOGY

    Neurotransmitters allow communication between brain regions. Alterations in neurotransmitter systems implicated in anxiety disorder pathogenesis include the monoamines serotonin (5-hydroxytryptamine or 5-HT), norepinephrine, and dopamine. Aberrant limbic signaling is associated with decreased inhibitory signaling by gamma-amino-butyric acid (GABA) or increased excitatory neurotransmission by glutamate. Many other neurotransmitter systems participate in the modulation of fear and anxiety, including the neuropeptide substances P, N, and Y; corticotropin-releasing factor (CRF); and endocannabinoids. Abnormalities in these systems are associated with structural and functional alterations in specific brain areas, such as the amygdala, prefrontal cortex, locus coeruleus, and hippocampus, and represent the therapeutic targets of drug therapy [70].

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  26. Patients with panic disorder/agoraphobia

    ETIOLOGY AND PATHOPHYSIOLOGY

    Patients with panic disorder/agoraphobia have shown subclinical abnormalities in balance system function that seemed to influence agoraphobia severity and contribute to dizziness and disorientation symptoms in complex sensory environments (e.g., shopping malls, traffic, crowds). These patients also display greater balance control reliance on non-vestibular, proprioceptive, visually dependent cues and greater balance system reactivity to peripheral visual stimulation. These possibly link to a more active visual alarm system involving visual, vestibular, and limbic areas. Patients with panic disorder/agoraphobia also show high sensitivity to light or brightness stimuli with photophobic behavior and abnormal retinal and pupillary reflex responses possibly linked to serotonergic and/or dopaminergic dysfunction. This overall amplified sensitivity to environmental stimuli suggests that agoraphobia involves activation of complex systems beyond panic attack fear and behavioral avoidance, including emotional responses to destabilizing/distressing environmental stimuli and operant-learning avoidance of experiences that provoke this distress [86].

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  27. Hyperactivity in all of the following brain regions is believed to be the underlying pathophysiology of specific phobia, EXCEPT:

    ETIOLOGY AND PATHOPHYSIOLOGY

    Amygdala, anterior cingulate cortex, and insula hyperactivity is believed to be the underlying pathophysiology of specific phobia. Neuroimaging studies have shown increased amygdala activation with exposure to phobic-relevant cues, and heightened activity in thalamic, insula, and dorsal anterior cingulate cortex regions [93,94,95]. Meta-analyses suggest the left amygdala/globus pallidus, left insula, right thalamus, and cerebellum regions are all more active among patients with a phobia compared with controls when exposed to phobic-relevant stimuli. Acute, exaggerated parasympathetic nervous system activity with exposure to stimuli is thought to underlie the vasovagal syncope experienced by up to 80% of people with blood-injection-injury phobia [96]. Exposure-based therapy leads to deactivation in the right frontal cortex, limbic cortex, basal ganglia, and cerebellum, and increased activity in the thalamus [97].

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  28. In the DSM-5, duration criteria for several anxiety disorders were extended to six months or longer to minimize overdiagnosis of transient symptoms, applied to all ages.

    CLINICAL AND DIAGNOSTIC FEATURES

    To better reflect current thinking on anxiety disorders, the DSM-5 made several important changes from the 1994 DSM-IV and its 2000 text revision [32,101]. As noted, the chapter on anxiety disorders no longer includes OCD, PTSD, and acute stress disorder. New sections were added for these conditions: obsessive-compulsive and related disorders and trauma- and stressor-related disorders. Duration criteria for several anxiety disorders were extended to six months or longer to minimize overdiagnosis of transient symptoms, applied to all ages.

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  29. The DSM-5 diagnostic criteria for which anxiety disorder remains unchanged from previous editions?

    CLINICAL AND DIAGNOSTIC FEATURES

    With agoraphobia, specific phobia, and SAD, the requirement that patients recognize their anxiety as excessive or unreasonable has been eliminated. This change was based on evidence that individuals with such disorders often overestimated the danger in "phobic" situations and that older individuals often misattributed "phobic" fears to aging. Instead, the anxiety must be out of proportion to the actual situational danger or threat, with consideration of cultural contextual factors [102].

    The DSM-5 (and previous DSM editions) has been criticized for emphasis on reliability at the expense of diagnostic validity and for use of symptom-based diagnosis when symptoms alone may not best inform treatment selection. In response, the National Institute of Mental Health is developing the Research Domain Criteria, a new taxonomy for mental disorders that draws from genetics, neuroscience, and behavioral science [103]. Additionally, the DSM-5-TR, which was released in March 2022, includes the addition of prolonged grief disorder; the inclusion of symptom codes for suicidal behavior and nonsuicidal self-injury; refinement of criteria; and comprehensive literature-based updates to the text [104].

    GAD is characterized by excessive and inappropriate worrying that is persistent and not restricted to particular circumstances. Patients have physical anxiety symptoms and key psychologic symptoms. GAD is often comorbid with major depressive disorder, panic disorder, phobia, health anxiety, and OCD [3]. The DSM-5 diagnostic criteria for GAD remain unchanged from previous editions [2,102]:

    • Excessive anxiety and worry (apprehensive expectation) over a number of everyday concerns (e.g., school/work performance)

    • Individual finds it difficult to control the worry

    • Excessive anxiety and worry are associated with three or more of the following six symptoms, with at least some occurring more days than not for at least six months:

      • Restlessness, feeling "on edge"

      • Easily fatigued

      • Difficulty concentrating

      • Irritability

      • Muscle tension

      • Sleep disturbance (difficulty falling or staying asleep, restless sleep)

    • The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning

    • Symptoms not better explained by another mental disorder

    • The disturbance is not attributable to the physiologic effects of a substance or another medical condition

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  30. Panic attacks often peak by 30 minutes and last around 3 to 4 hours.

    CLINICAL AND DIAGNOSTIC FEATURES

    Panic attacks are abrupt, unexpected periods of intense fear or discomfort with multiple physical or psychologic anxiety symptoms, often peaking by 10 minutes and lasting around 30 to 45 minutes. Panic disorder is characterized by recurrent unexpected surges of severe anxiety (panic attacks). As noted, most patients develop a fear of having further panic attacks. The extent of anticipatory anxiety between attacks varies, and patients may alter their behavior to reduce the recurrence risk [2,3].

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  31. In order for a diagnosis of panic disorder to be made, the symptoms must not be attributable to substance-related effects, other medical conditions, or other psychiatric disorders.

    CLINICAL AND DIAGNOSTIC FEATURES

    The symptoms must not be attributable to substance-related effects, other medical conditions, or other psychiatric disorders. Up to 70% of patients report a history of at least one nocturnal panic attack [106]. Patients may present with symptoms suggestive of heightened sympathetic nervous system activity such as palpitations, increased systolic blood pressure, hyperventilation, sweating, or flushing. Other common symptoms include chest pain and discomfort, dizziness, and paraesthesias, while gastrointestinal symptoms such as nausea and vomiting are more common among men [2,107].

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  32. Panic attack and trauma processing may be similar, with panic attack and PTSD trauma memories sharing the characteristics of reliving and disorganization.

    CLINICAL AND DIAGNOSTIC FEATURES

    Intense, disorganized recollections, a core symptom of PTSD, are thought to result from inadequate processing of trauma information. A first panic attack resembles trauma; both are unexpected, frightening, and subjectively life-threatening events. Like PTSD, panic disorder with agoraphobia also involves fear conditioning after the first event. Therefore, panic attack and trauma processing may be similar, with panic attack and PTSD trauma memories sharing the characteristics of reliving and disorganization. A comparison of panic memories and PTSD trauma memories did not find differences between groups in reliving intensity and disorganization levels, suggesting that panic attacks may affect information processing similarly to a traumatic event [109,110].

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  33. Fear of one's panic attacks, and avoidance of places or situations they may occur, best describes

    CLINICAL AND DIAGNOSTIC FEATURES

    Agoraphobia is defined as the fear of panic attacks occurring in places or situations from which escape might be difficult or embarrassing or where help may not be available. These situations can include crowds, going outside the home, or using public transportation and are either avoided or endured with significant personal distress [3]. Agoraphobia can become severely disabling, and more than 33% of patients diagnosed with agoraphobia cannot endure leaving their home environment. Roughly 66% of patients with panic disorder develop agoraphobia [2].

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  34. Temperament is shown to influence agoraphobia severity, with extroverted temperament significantly associated with the presence and severity of agoraphobic situational avoidance.

    CLINICAL AND DIAGNOSTIC FEATURES

    Major personality dimensions, such as introversion and neuroticism, have been studied for contribution to the risk of developing agoraphobia and other anxiety disorders. Genetic factors that influence individual variation in extraversion and neuroticism have been found to account entirely for genetic liability in SAD and agoraphobia but not animal phobia, emphasizing the importance of both introversion (low extraversion) and neuroticism as risk factors [115]. Situational avoidance is the most disabling aspect of agoraphobia. Temperament is shown to influence agoraphobia severity, with introverted temperament significantly associated with the presence and severity of agoraphobic situational avoidance [9].

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  35. SAD is the psychiatric diagnosis for simple shyness.

    CLINICAL AND DIAGNOSTIC FEATURES

    SAD is often misconstrued as mere shyness but can be considerably disabling and produce much greater distress and more severe symptoms. SAD is characterized by a marked, persistent, and unreasonable fear of being observed or evaluated negatively by other people in social or performance situations, which is associated with physical and psychologic anxiety symptoms. Feared situations, such as speaking to unfamiliar people or eating in public, are either avoided or are endured with significant distress [3]. Social phobia has been renamed SAD to reflect a new, broader understanding of the condition in a variety of social situations.

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  36. A core fear in patients with SAD is

    CLINICAL AND DIAGNOSTIC FEATURES

    Patients with SAD highly inflate perceived social costs from committing hypothetical blunders. Accounting for much of this social cost inflation are concerns about revealing self-flaws and, in particular, concerns over appearing socially incompetent [117].

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  37. The median age of onset with specific phobia is 3 years.

    CLINICAL AND DIAGNOSTIC FEATURES

    The median age of onset with specific phobia is 13 years [2]. According to the DSM-5, specific phobia is diagnosed when the following criteria are met [2]:

    • Marked fear or anxiety about a specific object or situation (e.g., flying, seeing blood)

    • Phobic object or situation almost always provokes immediate fear or anxiety and is actively avoided or endured with marked fear or anxiety

    • Fear or anxiety out of proportion to the actual danger posed by the specific object or situation

    • The fear, anxiety, or avoidance is persistent, typically at least six months

    • Marked distress or functional impairment

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  38. Which of the following is NOT a common feature of adult SEPAD?

    CLINICAL AND DIAGNOSTIC FEATURES

    SEPAD is characterized by fear or anxiety concerning separation from those to whom an individual is attached. Common features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential harms to attachment figures or untoward events that might result in separation [3].

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  39. In the DSM-5, selective mutism is categorized in the section Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence, removing it from the umbrella of anxiety disorders.

    CLINICAL AND DIAGNOSTIC FEATURES

    Separation anxiety disorder and selective mutism were included in the DSM-IV section Disorders Usually First Diagnosed in Infancy, Childhood, or Adolescence, but were classed as anxiety disorders and moved to the anxiety disorder section in the DSM-5 [102]. The majority of children with selective mutism are anxious, and while selective mutism is now considered an anxiety disorder, it remains a disorder primarily of childhood and is beyond the scope of this course [102].

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  40. What is the first step in the management of patients presenting with anxiety symptoms?

    ASSESSMENT

    The management of patients presenting with anxiety symptoms should initially follow the flow of these five components [120]:

    1. Screen for anxiety and related symptoms.

    2. Consider differential diagnosis and severity, impairment, and comorbidity.

    3. Identify specific or multiple anxiety disorder(s).

    4. Initiate psychologic and/or pharmacologic treatment.

    5. Perform follow-up.

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  41. All of the following statements regarding anxiety disorder recognition and diagnosis in primary care settings are true, EXCEPT:

    ASSESSMENT

    In primary care settings, panic disorder prevalence is around 10%, with GAD co-occurring in 68% of patients with panic disorder and in 38.6% of those with major depression [34,122]. The American Academy of Family Physicians states that rates of missed diagnoses and misdiagnosis of GAD and panic disorder are high in primary care, with symptoms often ascribed to physical causes [121]. One study of older patients with GAD found low rates of anxiety symptom recording (34%) and anxiety disorder diagnosis (9%) despite high levels of healthcare utilization [123]. In the current managed care environment, anxiety is usually treated in the primary care setting, and given the increasing time constraints imposed on primary care providers, it is not surprising that anxiety disorders are under-recognized and undertreated [70].

    Many patients with anxiety and depressive symptoms do not seek help, and in those who do, anxiety symptoms are often not the presenting complaint. Patients and providers often have difficulty initiating discussion of emotional problems and distress. Primary care providers with greater sensitivity to nonverbal communications have been found more likely to detect and diagnose anxiety, while those tending to "blame" patients make fewer psychologic inquiries and are less accurate in detecting distress [3,124].

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  42. Symptom presentation is influenced by cultural factors, and in some cultures, anxiety may be expressed through somatic symptoms, such as musculoskeletal pain and fatigue.

    ASSESSMENT

    Healthcare providers can create a more comfortable environment for a patient of another culture by acknowledging the impact of culture and cultural differences on physical and mental health. Symptom presentation is influenced by cultural factors, and in some cultures, anxiety may be expressed through somatic symptoms, such as musculoskeletal pain and fatigue. Providers may consider starting the conversation with the patient by focusing on physical symptoms. The concept of anxiety also varies across cultures, and patients may not seek medical treatment unless symptoms manifest as psychosis, conversion disorders, or significant physical ailments.

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  43. When obtaining a patient history for individuals experiencing anxiety, patients should be assessed for onset of anxiety symptoms, duration (remission or persistent), association with life events or trauma, level of distress, and effect on current functioning.

    ASSESSMENT

    A patient history is performed to assess patient and family history for clinically relevant information. Patients should be assessed for onset of anxiety symptoms, duration (remission or persistent), association with life events or trauma, level of distress, and effect on current functioning (academic, occupational, relationships, leisure activities, role functioning). Also inquire about a personal history of physical or emotional trauma, anxiety or mood disorders, medications or therapies, and patient response. Family history should be assessed for anxiety, mood, and substance use disorders [2]. Screening for depression is very important, given its high comorbidity rate and associated risk of suicidal behavior [129].

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  44. Avoidant personality disorder should be ruled out in the differential diagnosis of

    ASSESSMENT

    A diagnosis of SAD should rule out avoidant personality disorder. Some symptoms of avoidant personality disorder resemble SAD, such as a pervasive pattern of social inhibition, feelings of inadequacy, and hypersensitivity to negative evaluation. However, avoidant personality disorder is distinguished by non-social avoidance that extends to novel situations and positive affect. Roughly 36% of patients with SAD are comorbid for avoidant personality disorder, and some believe avoidant personality disorder is a more severe variant of SAD [130,131].

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  45. Which of the following medications/supplements has anxiety side effects?

    ASSESSMENT

    It is important to rule out medication side effects as the underlying cause of anxiety by obtaining a complete list of currently used prescribed, over-the-counter, and herbal medications. Examples of common medications with anxiety side effects are asthma medications (e.g., albuterol, theophylline), herbal medicines (St. John's wort, ginseng, ma huang), corticosteroids, and antidepressants [2].

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  46. CBT with some variant of exposure is the first-line psychotherapy approach for most pathologically anxious patients.

    GENERAL TREATMENT CONSIDERATIONS

    CBT, which includes an exposure therapy component, is used to address and work through maladaptive beliefs and avoidance behaviors that reinforce pathology surrounding fear-eliciting stimuli. CBT with some variant of exposure is the first-line psychotherapy approach for most pathologically anxious patients. Pharmacotherapy, also a first-line treatment for anxiety disorders, uses various agents to induce rapid anxiolytic effects (e.g., benzodiazepines, some anti-epilepsy drugs) or agents that require prolonged, long-term treatment (e.g., antidepressants) to attenuate symptoms of pathologic fear and anxiety [136].

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  47. Addressing the underlying pathophysiology in anxiety disorders requires

    GENERAL TREATMENT CONSIDERATIONS

    Advances in anxiety disorder neuroscience have increasingly pointed to the necessary role of fear extinction learning (through exposure therapy) in addressing underlying pathophysiology. While efficacy is shown with CBT and exposure, patients can have difficulty with the demanding and exhausting therapy process, and many who do manage to complete therapy respond partially and relapse with time. Efforts to improve CBT/exposure outcomes have led to the investigation of augmenting agents. In contrast to standard anti-anxiety drugs, these agents are not anxiolytic but are used to promote and accelerate long-term adaptive changes in brain function initiated by successful exposures [137].

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  48. Treatment dropout is very high in exposure therapy, as patients repeatedly confront (with graded intensity) the situations or objects that trigger their greatest fear or panic response.

    GENERAL TREATMENT CONSIDERATIONS

    Treatment refusal and attrition are significant problems. Patients with anxiety disorders show treatment refusal rates of 25% to 30% and treatment dropout rates of 10% to 82% [139]. Treatment dropout is very high in exposure therapy, as patients repeatedly confront (with graded intensity) the situations or objects that trigger their greatest fear or panic response. The intensity of distress during exposure can overwhelm patients, and with avoidance the hallmark feature of most anxiety disorders, attrition is significant [2,139]. Attrition can interfere with evaluating treatment efficacy (or the lack thereof), and unless explicit in study reporting, can be misleading. Attrition is also a clear concern in the clinical care of patients with anxiety.

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  49. When present as a comorbidity to an(other) anxiety disorder, which condition highly predicts worse symptom chronicity and poor treatment response and patient outcome?

    GENERAL TREATMENT CONSIDERATIONS

    Pathologic SEPAD is associated with a pervasive negative influence on treatment response. Comorbid SEPAD is highly correlated with poor treatment response and patient outcomes across a range of anxiety and mood disorders. SEPAD negatively impacts response to major depression treatment and is linked to worse symptom chronicity and quality of life. SEPAD decreases CBT response and predicts worse outcomes in patients treated for panic disorder, GAD, or SAD. SEPAD also predicts nonresponse to selective serotonin re-uptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs) in patients with panic disorder with agoraphobia [98,140].

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  50. Problematic, excessive drinking clearly disrupts treatment response, but social drinking is generally fine during the treatment of panic disorder.

    GENERAL TREATMENT CONSIDERATIONS

    Problematic, excessive drinking clearly disrupts treatment response, but social drinking can also aggravate panic disorder and probably other anxiety syndromes. The short-acting effects of alcohol wear off rapidly, followed by rebound to a state of hyper-excitability that may be more problematic for patients with anxiety. This can occur with one to two drinks in some patients, who often do not even consider this a contributing factor to their anxiety complaint. Explaining the simple physiology of rebound excitation after profound neuronal inhibition will often convince patients that alcohol may be sensitizing the neural circuits subserving their anxiety and that a trial period of abstinence is indicated [28].

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  51. Disorder-specific CBT is the standard of care for anxiety and depressive disorders.

    GENERAL TREATMENT CONSIDERATIONS

    CBT is not a single treatment approach but a process that addresses factors that caused and maintain patient anxiety symptoms. The classic CBT approach involves disorder-specific treatment protocols that target the symptoms and the cognitive, behavioral, and emotional vulnerabilities that underlie development and maintenance of each disorder. This approach reflects the assumption that each form of psychopathology has a distinct cognitive profile, to which CBT is tailored accordingly. Disorder-specific CBT is the standard of care for anxiety and depressive disorders [152]. However, there are common components of CBT used in anxiety disorders (Table 2) [120].

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  52. Which of the following is a component of CBT used for anxiety disorders?

    GENERAL TREATMENT CONSIDERATIONS

    COMMON COMPONENTS OF CBT USED IN THE TREATMENT OF ANXIETY DISORDERS

    Cognitive Strategies
    Cognitive restructuring, behavioral experiments, and related strategies target exaggerated perception of danger (e.g., fear of negative evaluation in SAD).
    Therapy provides corrective information regarding the level of threat and can also target self-efficacy beliefs.
    Arousal Management
    Relaxation and breathing control skills help control increased anxiety levels.
    Exposure
    Encourage patients to face fears.
    Patients learn corrective information through experience.
    Extinction of fear occurs through repeated exposure.
    Successful coping enhances self-efficacy.
    Safety Response Inhibition and Surrender of Safety Signals
    Patients wean from and relinquish use of their usual anxiety-reducing safety signals and behaviors (e.g., presence of a companion, need for reassurance, knowing the location of nearest exit or toilet), which decreases negative reinforcement.
    Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy, allowing patients to learn adaptive self-efficacy beliefs.
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  53. Which of the following most accurately reflects anxiety disorder outcome research?

    GENERAL TREATMENT CONSIDERATIONS

    Psychotherapy and drug therapy show similar efficacy in most anxiety disorders. Psychotherapy plus drug (combination) therapy outcomes vary and are conflicting, and current evidence does not support routine combination therapy as initial treatment. However, patients lacking response to CBT or drug therapy may benefit from adding the other modality [120].

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  54. Mindfulness is not effective (and may be detrimental) in the treatment of GAD and panic disorder.

    GENERAL TREATMENT CONSIDERATIONS

    Mindfulness involves attending to relevant aspects of experience in a non-judgmental manner. The goal of mindfulness is to maintain moment-by-moment awareness; disengage oneself from strong attachment to beliefs, thoughts, or emotions; and develop a greater sense of emotional balance and well-being. An aim of mindfulness practice is to take greater responsibility for one's life choices. Some evidence supports the efficacy of this approach in GAD and panic disorder [155,156,157].

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  55. Applied relaxation teaches patients to observe the first signs of a panic attack and apply a rapid and effective relaxation technique to cope with and abort panic symptoms before escalation into a panic attack.

    GENERAL TREATMENT CONSIDERATIONS

    Physiologic therapies involve physical training (e.g., breathing retraining, relaxation techniques, biofeedback) to help patients control physiologic anxiety symptoms. Hyperventilation and hypocapnia are identified factors in panic disorder development and maintenance; panic attacks can be caused by acute hypocapnia states in a positive feedback loop between hyperventilation and anxiety. Breathing training is used to ameliorate panic symptoms, but it shows mixed efficacy in panic disorder [162]. Progressive muscle relaxation teaches patients with panic to reduce general tension and achieve a body state that lowers the risk for panic-inducing stressors. Applied relaxation teaches patients to observe the first signs of a panic attack and apply a rapid and effective relaxation technique to cope with and abort panic symptoms before escalation into a panic attack. Applied relaxation is comparable to progressive muscle relaxation in reducing panic attacks [151].

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  56. In vivo exposure therapy involves patient immersion into a software-generated virtual world that allows them to confront their fears.

    GENERAL TREATMENT CONSIDERATIONS

    Exposure therapy is defined as any treatment that encourages patients to systematically confront feared stimuli, which can be external (e.g., feared objects, activities, situations) or internal (e.g., feared thoughts, physical sensations) [136]. Exposure therapy is an effective, empirically supported treatment modality for anxiety disorders and a core component of CBT. Variants of exposure therapy include:

    • In vivo exposure: Exposure that involves real-world confrontation of feared stimuli

    • Imaginal exposure: Vividly imagining and describing the feared stimulus, including details about external (sights, sounds) and internal (thoughts, emotions) cues

    • Virtual reality exposure: Patient immersion into a software-generated virtual world that allows them to confront their fears

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  57. Exposure therapies facilitate extinction learning by diminishing the association between the avoided situation and fear and promoting new learning of the true nonthreatening nature of the situation.

    GENERAL TREATMENT CONSIDERATIONS

    The success of exposure therapy occurs by targeting maladaptive learning and fear conditioning, core mechanisms implicated in anxiety disorder etiology and maintenance. Standard exposure therapy involves exposure to feared objects or situations and gradual elimination of safety behaviors—the subtle avoidance behaviors that temporarily diminish distress in feared situations but interfere with long-term anxiety reduction. Patients are encouraged to continue confronting the feared situations through exposure until substantive reductions in fear occur. Exposure therapies facilitate extinction learning by diminishing the association between the avoided situation and fear and promoting new learning of the true nonthreatening nature of the situation [164,165].

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  58. Although all major antidepressant classes are comparably effective against anxiety disorders, which of the following is recommended due to better safety and tolerability?

    GENERAL TREATMENT CONSIDERATIONS

    Antidepressants are generally recommended as first-line therapy for panic disorder because, unlike benzodiazepines, antidepressants treat comorbid depression and lack abuse risk and potential side effects of excessive sedation, cognitive impairment, and ataxia. All major antidepressant classes are comparably effective, but SSRIs and, increasingly, serotonin-norepinephrine reuptake inhibitors (SNRIs) are recommended over TCAs and MAOIs due to better safety and tolerability [172].

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  59. The only SSRI believed to lack pharmacologic activity beyond serotonin reuptake transporter inhibition is

    GENERAL TREATMENT CONSIDERATIONS

    It is now recognized that SSRIs differ in pharmacologic effect, including activity beyond SERT inhibition [179,180]:

    • Fluoxetine: Antagonist at 5-HT2C receptors, which enhances norepinephrine and dopamine release. Therapeutic effects may emerge more slowly than other SSRIs.

    • Sertraline (Zoloft): A weak dopamine transporter inhibitor, sigma-1 receptor activity. Along with fluoxetine, increases cortex monoamine levels to possibly explain patient reports of improved energy, motivation, and concentration.

    • Paroxetine (Paxil): A weak norepinephrine transporter inhibitor, which contributes to antidepressant effects. Muscarinic cholinergic receptor activity may underlie some sedative and anxiolytic effects.

    • Fluvoxamine (Luvox): Along with sertraline, has sigma-1 receptor activity that possibly contributes to the anxiolytic effects of both agents.

    • Citalopram (Celexa): Mild antihistamine properties not observed with escitalopram.

    • Escitalopram (Lexapro): Is considered the only SSRI without pharmacologic activity beyond SERT inhibition.

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  60. The benzodiazepine with greater efficacy in panic disorder is

    GENERAL TREATMENT CONSIDERATIONS

    Meta-analyses suggest alprazolam, lorazepam, and diazepam are effective but comparable in GAD efficacy, while clonazepam shows much greater efficacy in the treatment of panic disorder than alprazolam, lorazepam, and diazepam, which all have modest efficacy [224].

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  61. Which of the following reflects inappropriate benzodiazepine prescribing?

    GENERAL TREATMENT CONSIDERATIONS

    Benzodiazepine treatment of anxiety disorders is controversial. While effective in rapid anxiety reduction, the potential drawbacks with long-term use are substantial. These agents are indicated when potent, short-term anxiolytic effects are necessary to permit infrequent exposure to feared stimuli and potentially severe anxiety, such as airplane travel [121,129,136]. Clonazepam, lorazepam, and alprazolam are effective for short-term use in panic disorder, GAD, and SAD, but ineffective for, and potentially worsening, comorbid depression [28]. The rapid anxiolytic effects make benzodiazepines highly appealing to patients with anxiety, but aside from this specific context, benzodiazepine prescribing for as-needed use is discouraged [136,225,226]. Benzodiazepines can reinforce pill taking, serve as a safety signal that undermines self-efficacy, and become incorporated into conditioned fear responses; these concerns are heightened with as-needed use. On-demand dosing links pill taking to rapid anxiety reduction, powerfully reinforcing avoidance in anxiety-provoking situations and encouraging longer-term reliance on the drug. This iatrogenic effect also contributes to poor CBT response.

    The current recommended prescribing is for time-dependent use, instead of panic response-dependent use, to minimize the risks [121]. This would also seem to maximize risk of withdrawal syndrome from uninterrupted versus intermittent drug exposure.

    Benzodiazepines are also useful in the initial weeks of SSRI/SNRI initiation, to rapidly reduce anxiety and possible early anxiogenic medication side effects before the onset of SSRI/SNRI anxiolytic effects [121,129,136]. However, patients may discontinue the antidepressant when co-prescribed a rapidly effective benzodiazepine, believing the benzodiazepine's symptom relief makes the SSRI/SNRI unneeded. Supportive therapy with regular visits or phone contacts may also help patients remain adherent until the delayed onset of antidepressant benefits appears or early antidepressant side effects lessen [227].

    Another indication for benzodiazepine use is for the short-term relief (two to four weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress. Perhaps the greatest prescribing challenge with benzodiazepines is preventing short-term use from insidiously developing into long-term use. Patients with the most severe anxiety may obtain the greatest relief and become most hesitant to discontinue use [228]. In many cases, clinicians ignore the recommended two- to four-week prescribing limit, mainly because alternative options with superior anxiolytic effects are not available [229]. Clinicians intending to prescribe alprazolam should carefully consider the likelihood that its use will remain restricted to the very short term—a few days to a couple weeks—to see the patient through a crisis [228].

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  62. Which of the following statements regarding SSRI/SNRI withdrawal syndrome is TRUE?

    GENERAL TREATMENT CONSIDERATIONS

    A 2015 meta-analysis found SSRI withdrawal symptoms can occur with any SSRI but are exceedingly more frequent with paroxetine [248]. Common symptoms include dizziness, nausea, headache, confusion, low energy, weakness, sleep disturbance, flu-like symptoms, restlessness, agitation, anxiety, panic, anger, and irritability. Less common and more severe symptoms include electric-shock sensations, vertigo, paresthesias, intensified suicidal ideation, aggression, derealization, depersonalization, and visual/auditory hallucinations. Symptoms do not greatly differ between patients with anxiety versus mood disorders. The authors concluded that the typical SSRI withdrawal syndrome begins within a few days of cessation and lasts two to three weeks [248]. Variations include late onset and protracted duration up to one-year follow-up. Several cases of persistent postwithdrawal disorders induced by paroxetine have been described.

    Gradual tapering is a reasonable strategy but does not prevent the onset of SSRI withdrawal [248]. Patient characteristics that predict increased vulnerability are not known. Recognition of withdrawal symptoms requires careful exploration, as they can be misidentified as signs of impending relapse. Even when withdrawal symptoms are recognized, clinical management is hindered by the lack of research.

    SSRI cessation may trigger complex phenomena related or unrelated to the onset of withdrawal, such as hypomania, mania, and persistent postwithdrawal disorders. Iatrogenic comorbidity describes the lasting effects from treatment well beyond their time of administration, such as mood instability and high reactivity to environmental stimuli in persistent postwithdrawal disorders [248].

    Among 20 patients with remitted panic disorder with agoraphobia followed over one year after SSRI cessation, nine experienced SSRI withdrawal syndrome that subsided within one month [249]. Exceptions were three patients taking paroxetine, who experienced worsened mood, fatigue, and emotional lability with trouble sleeping, irritability, and hyperactivity. One patient prescribed clonazepam after three months of symptom persistence improved considerably but was later unable to discontinue clonazepam. A second patient did not improve with clonazepam or fluvoxamine, and symptoms subsided only with paroxetine reinstatement. In a third patient, clonazepam had little benefit, paroxetine reinstatement was refused, and symptoms persisted unchanged over one year [249].

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  63. The anxiety disorder medication with greatest lethality in overdose is

    GENERAL TREATMENT CONSIDERATIONS

    In some patients with anxiety disorder, and especially those with depressive comorbidity, consideration of overdose fatality is necessary when deciding on therapy options. Lethality rates from intentional overdose involving single medication ingestions of agents commonly prescribed for depression and anxiety were calculated from data obtained during the period 2000–2014 [252]. TCAs remain the most lethal antidepressants, with fatality rates from 31–142 per 10,000 ingestions. Amitriptyline is associated with the greatest lethality in overdose and alone accounted for 37% of all deaths from antidepressants [252]. Lithium, bupropion, venlafaxine, quetiapine, and valproic acid had rates of 6.9–12.0 per 10,000 ingestions, while citalopram and fluvoxamine had rates of 3.9–4.1 per 10,000. Fluoxetine, sertraline, paroxetine, and escitalopram had the lowest overdose lethality rates at 0.79–1.34 per 10,000 ingestions [252].

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  64. Cognitive therapy/CBT techniques may be especially helpful for generalized anxiety in early life.

    TREATMENT OF GENERALIZED ANXIETY DISORDER

    Cognitive therapy/CBT techniques may be especially helpful for generalized anxiety in later life [120].

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  65. In the treatment of generalized anxiety disorder, which of the following is NOT a treatment option?

    TREATMENT OF GENERALIZED ANXIETY DISORDER

    Several options as second-line agents have efficacy in GAD comparable to first-line agents but possess potential side effects or other risks that preclude first-line use [120]. Benzodiazepines would be considered first in most cases, except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy, but given the metabolic concerns associated with this atypical antipsychotic, it should be reserved for patients who lack response or cannot tolerate antidepressants or benzodiazepines [120]. It is important to note that drugs such as beta-blockers (e.g., propranolol) prescribed to address the physical symptoms of anxiety are ineffective in the treatment of GAD [243].

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  66. Research indicates that pharmacotherapy alone is optimal care for patients with panic disorder.

    TREATMENT OF PANIC DISORDER

    A meta-analysis found sufficient evidence that combined treatment is superior in panic disorder, with effects of combined psycho- and pharmacotherapy treatment versus placebo about twice as large as pharmacotherapy alone versus placebo [279]. The results also suggest that the effects of pharmacotherapy and psychotherapy are largely independent from each other and roughly equal in contribution to the effects of combined treatment. The effects remain strong and significant up to two years post-treatment. As such, monotherapy may not constitute optimal care [279].

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  67. Which of the following is a first-line drug recommended for the treatment of panic disorder?

    TREATMENT OF PANIC DISORDER

    The first-line drugs recommended for the treatment of panic disorder are SSRIs or venlafaxine XR [120]. Research suggests that the largest effect size is found with clonazepam, followed by venlafaxine and fluoxetine [224]. Despite a sizeable number of pharmacologic options, less than 50% of patients with panic disorder experience full and sustained remission to first-line medication therapy [287].

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  68. Which of the following statements regarding the psychologic treatment for SAD is TRUE?

    TREATMENT OF SOCIAL ANXIETY DISORDER

    CBT is the criterion-standard psychologic treatment for SAD. Cognitive techniques that address SAD include restructuring and challenging maladaptive thoughts, and the behavioral component typically involves exposure therapy. The efficacy of CBT is supported by many randomized controlled trials, with outcomes that vary but are typically similar to pharmacotherapy. Some reports suggest that, after treatment discontinuation, gains achieved with CBT may persist longer than those achieved with pharmacotherapy. CBT for SAD can be administered in group or individual formats. Although some studies have reported that individual CBT is superior to group CBT, meta-analyses have failed to find significant differences in efficacy between the two modalities. There is evidence to support the effectiveness of exposure therapy alone, but efficacy compared with CBT is equivocal [120].

    Several CBT variants have been examined. Videotaped feedback was not shown to enhance the effects of exposure-based treatment. However, CBT with virtual reality exposure was found more effective than wait-list control and as effective as CBT with imaginal or in vivo exposure according to two meta-analyses [120].

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  69. Exposure-based therapies are the treatments of choice and show a high degree of successful remission for all specific phobias.

    TREATMENT OF SPECIFIC PHOBIA

    Exposure-based therapies are the treatments of choice and show a high degree of successful remission for all phobias. In vivo exposure and virtual reality exposure can be effective, with in vivo exposure superior to imaginal and virtual reality exposure at post-treatment but not at follow-up [307]. The effectiveness of exposure-based therapy is enhanced when exposure sessions are grouped closely together; when exposure is prolonged, real (not imagined), and provided in different settings; and when there is some degree of therapist involvement instead of being entirely self-directed. A greater number of sessions have been shown to predict more favorable outcomes. There is no evidence that flooding is more effective, and patients usually find graded, progressive exposures more tolerable [307].

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  70. Which of the following statements regarding the treatment of specific phobia is TRUE?

    TREATMENT OF SPECIFIC PHOBIA

    Exposure-based therapies are the treatments of choice and show a high degree of successful remission for all phobias. In vivo exposure and virtual reality exposure can be effective, with in vivo exposure superior to imaginal and virtual reality exposure at post-treatment but not at follow-up [307]. The effectiveness of exposure-based therapy is enhanced when exposure sessions are grouped closely together; when exposure is prolonged, real (not imagined), and provided in different settings; and when there is some degree of therapist involvement instead of being entirely self-directed. A greater number of sessions have been shown to predict more favorable outcomes. There is no evidence that flooding is more effective, and patients usually find graded, progressive exposures more tolerable [307].

    A variety of psychotherapeutic options have been found effective for the treatment of specific phobias, with some approaches recommended for particular phobias (Table 4) [120]. For blood-injection-injury phobias, an effective approach is combining exposure therapy with muscle tension exercises (applied tension) designed to prevent fainting. Using stress-reducing medical devices, such as decorated butterfly needles and syringes, has significantly reduced needle phobia and stress in pediatric and adult patients. With dental phobias, use of CBT can reduce avoidance of oral injections and decrease patient anxiety [120,307].

    Long-term treatment of specific phobia is rare. CBT and exposure therapies show sustained benefits at long-term follow-up assessments following a time-limited course of treatment [120].

    Pharmacotherapy has a minimal role in specific phobia treatment, largely from the lack of drug therapy research and the success of exposure therapies. Alprazolam benefit was studied in 28 women with flying phobia during two air travel exposures, one week apart. Compared with subjects given pre-flight placebo for both flights, those receiving alprazolam before the first flight had less anxiety and symptoms but greater heart and respiratory rates. Those given alprazolam had a substantial increase in panic attacks during the second flight compared with the first flight (71% vs. 7%), greater overall anxiety, and further elevation in heart rate. Alprazolam increased physiologic activation under acute stress conditions and hindered the therapeutic effects of exposure therapy for flying phobia [120,308]. These findings require replication to determine clinical utility.

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  71. Which of the following psychologic treatment approaches has been identified as effective in the treatment of phobia specific to small animals?

    TREATMENT OF SPECIFIC PHOBIA

    PSYCHOLOGIC TREATMENTS EFFECTIVE IN SPECIFIC PHOBIA

    Treatment ApproachPhobia(s)
    Exposure-based treatmentsAll specific phobias
    Virtual reality exposureHeights, flying, spiders, claustrophobia
    Computer-based self-help programsSpiders, flying, small animals
    Applied muscle tension (i.e., exposure with muscle tension exercises)Blood-injection-injury type
    Cognitive therapy and exposureDental, flying
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  72. Patients with SEPAD show poor response to standard CBT and exposure-based therapies.

    TREATMENT OF SEPARATION ANXIETY DISORDER

    As mentioned, the presence of pathologic separation anxiety has a pervasive negative influence on treatment response in patients with diverse anxiety and mood disorders receiving standard therapies. Patients with SEPAD show poor response to standard CBT and exposure-based therapies. This poorer treatment response may reflect the difficulties these patients experience forming and maintaining attachments, including therapeutic relationships. Growing evidence points to the incompatibility in applying the prevailing fear extinction model of anxiety to patients with SEPAD. This pathophysiologic model emphasizes desensitization to threatening stimuli. While theoretically and empirically supported in other anxiety disorders, this model does not consider the role of earlier childhood SEPAD in adult panic disorder and other anxiety disorders [98].

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  73. Panic-focused psychodynamic psychotherapy is best described as

    TREATMENT OF SEPARATION ANXIETY DISORDER

    The unmet need for SEPAD-specific treatment has led to psychotherapies that focus on relationships and separation anxiety. These approaches use the therapist-patient relationship to recapture and better understand important elements of earlier pathologic parent-child relationships. Panic-focused psychodynamic psychotherapy is an affect-focused therapy that specifically targets separation anxiety as a core component of panic disorder. Preliminary efficacy is shown in patients with prominent separation anxiety symptoms across different anxiety and mood disorders. High separation anxiety levels constitute a central organizing element in patient self-perception as incompetent and unable to manage developmentally normative tasks without the presence of their central attachment figures. Panic-focused psychodynamic psychotherapy emphasizes free association, centrality of transference, unconscious thoughts that underlie physical sensations of panic, and difficulty with separation and autonomy. The therapist focuses on these processes as they relate to panic symptoms. Common themes of difficulty with separations and unconscious rage inform interpretive interventions. The pre-determined 24-session, 12-week time limit enhances the opportunity to work with separation anxiety and permits the re-experiencing and better understanding [98].

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  74. In exposure augmentation using D-cycloserine (DCS),

    EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

    Dosing and dose timing of DCS is essential. Most trials reporting positive results used low-dose DCS (50–250 mg) one to two hours before three to five exposure sessions. Studies with negative results often used higher doses (≥250 mg), chronically (before 12 exposures), and more than one to two hours before an exposure. Higher-dose DCS shows weaker NMDA partial agonist or antagonist effects. Key extinction learning processes occur hours following exposure, and DCS blood concentration peaking at four to six hours makes it more effective taken within one to two hours before exposure for peak activity to coincide with key extinction processes. Repeated DCS use can desensitize the NMDA receptor complex, leading DCS to effectively work as an NMDA antagonist. Long-term antidepressants can induce neurochemical changes at the glycine binding site of the NMDA receptor complex, which alters the action of DCS. Therefore, use of DCS should consider the narrow therapeutic window and the need to be administered without concomitant medication, acutely, and at low doses one to two hours pre-exposure [310].

    DCS is associated with serious risks. DCS not only enhances cognitive processes during fear extinction learning but also during fear memory reconsolidation, thus improving good exposures and worsening bad exposures. If fear-inducing stimulus re-exposure during fear memory reactivation is too brief relative to the strength of fear conditioning or if fear decrease during exposure is inadequate, little extinction is induced and DCS can augment the process of fear memory reconsolidation to worsen symptoms [310].

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  75. Panic attacks that awaken people at night only occur during non-REM sleep, when deep relaxation and slowed breathing lead to rising CO2 levels that trigger a false suffocation alarm.

    EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

    Panic disorder and sensitivity to increased carbon dioxide (CO2) levels common in patients with panic disorder may represent pathologically amplified survival mechanisms. Panic disorder reflects a "fight-or-flight" response, and CO2 hypersensitivity is an evolutionary carry-over from when alarm response to dwindling oxygen helped ensure survival. Panic attacks that awaken people at night only occur during non-REM sleep, when deep relaxation and slowed breathing lead to rising CO2 levels that trigger a false suffocation alarm [317].

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  76. When given after resolution of symptoms, cannabidiol enhances consolidation of extinction learning.

    EMERGING THERAPIES AND NOVEL TREATMENT APPROACHES

    In a series of randomized controlled trials using fear-conditioning paradigms, subjects who received cannabidiol (vs. placebo) all showed successful conditioning, extinction, and recall. When given after resolution of symptoms, cannabidiol enhanced consolidation of extinction learning. Cannabidiol administered pre- or post-extinction reduced the reinstatement of autonomic contextual responding. No acute effects of cannabidiol were found on extinction. These results are the first evidence that cannabidiol may enhance consolidation of extinction learning in humans, suggesting cannabidiol may have potential as an adjunct to extinction therapies for anxiety disorders [326].

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  77. Myo-inositol was found beneficial in randomized controlled trials for all of the following, EXCEPT:

    COMPLEMENTARY/ALTERNATIVE THERAPIES

    Several randomized controlled trials have been conducted using placebo or active controls. In 21 patients with panic disorder with or without agoraphobia given inositol 12 g/day or placebo for four weeks, significant decreases were found in the frequency and severity of panic attacks and agoraphobia severity with inositol relative to placebo [335]. Another randomized controlled trial compared myo-inositol 18 g/day with fluvoxamine 150 mg/day in patients with panic disorder with or without agoraphobia. Both drugs led to significant but comparable improvements in anxiety symptoms/severity, agoraphobia symptoms/severity, and global impression. In the first month, reduction in the number of panic attacks per week was significantly greater with inositol than fluvoxamine (4.0 vs. 2.4). Nausea and fatigue were significantly more common with fluvoxamine [336].

    Other randomized controlled trials found that myo-inositol 12 g/day in 28 patients with major depression significantly reduced Hamilton Depression Rating Scale scores (vs. placebo) after four weeks; and 18 g/day given to patients with OCD for six weeks led to significant reductions in OCD symptom scores (vs. placebo) [335]. A review of supplements and herbal therapies with purported anxiolytic efficacy concluded myo-inositol was one of very few with demonstrated effectiveness [337]. The published research needs larger trials but is intriguing in light of a study in which patients with severe depression receiving treatment with rTMS showed significantly elevated prefrontal cortex myo-inositol levels, and this elevation correlated with extent of clinical improvement [338]. A meta-analysis of inositol for depression and anxiety disorders found that the agent may be particularly beneficial for treatment of depression [339].

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  78. Silexan, a lavender oil capsule preparation, appears to be an effective and well-tolerated alternative to benzodiazepines for GAD treatment.

    COMPLEMENTARY/ALTERNATIVE THERAPIES

    A six-week randomized controlled trial compared silexan, a lavender oil capsule preparation, with lorazepam in GAD treatment efficacy. Both treatment groups showed similar reductions on the primary anxiety measure (HAM-A) and similar and comparable reductions on measures of somatic anxiety, psychic anxiety, anxiety self-rating, impression of illness severity, sleep quality, and other scales. Silexan appears to be an effective and well-tolerated alternative to benzodiazepines for GAD treatment [343]. A 10-week randomized controlled trial compared silexan with paroxetine and placebo in GAD treatment efficacy. Participants received 80 mg or 160 mg silexan, 20 mg paroxetine, or placebo once daily for 10 weeks [344]. The primary outcome measured was HAM-A total score reduction between baseline and treatment end. A total of 60.3% of participants in the silexan 160 mg group showed a HAM-A total score reduction greater than 50% of the baseline value compared with 51.9% in the silexan 80 mg group, 34.1% in the paroxetine group and 37.8% in the placebo group. Silexan additionally showed a pronounced antidepressant effect and improved general mental health and health-related quality of life. Rates of adverse effects were comparable among the silexan and placebo groups and lower for the paroxetine group [344].

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  79. A growing body of literature has identified anxiolytic effects of resistance exercise after both single sessions and long-term training.

    COMPLEMENTARY/ALTERNATIVE THERAPIES

    Resistance exercise (i.e., strength training) includes a broad group of activities that evoke repeated muscle action against resistances above those encountered in daily life. A growing body of literature has identified anxiolytic effects of resistance exercise after both single sessions and long-term training. This research has shown that resistance training at a low-to-moderate intensity produces the most reliable and robust decreases in anxiety. Higher intensity has shown either no change or increased anxiety from baseline. One caveat is most of this research involved participants with state (not trait) anxiety [345].

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  80. The complementary therapy with strongest evidence of safety and efficacy in anxiety disorders is

    COMPLEMENTARY/ALTERNATIVE THERAPIES

    Yoga is an ancient mind/body practice that involves different techniques in physical postures, controlled breathing, deep relaxation, and meditation that have positive and specific influences. Research on yoga has demonstrated significant improvements in emotional self-regulation with consequent reductions in depression, stress, and anxiety levels and improvements in mood, quality of life, and well-being [346]. Several studies have found significant anxiolytic effects with yoga in patients with GAD or panic disorder, and it is considered the complementary therapy with strongest evidence of safety and efficacy in anxiety disorders.

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