Elsevier Logo

ThisiscontentfromClinicalKey

Want more answers?

Sign up for your free ClinicalKey trial today!  Your first step in getting the right answers when you need them. ClinicalKey is a clinical knowledge solution designed to help healthcare professionals and students find the right answers by providing in-depth, evidence-based knowledge – all from one resource.

Dec.17.2020View related content

Generalized anxiety disorder

Synopsis

Key Points

  • Generalized anxiety disorder is a mental disorder characterized by continuous and uncontrolled worrying without a significant cause
    • Symptoms are present on most days for at least 6 months to confirm the diagnosis r1
  • Psychiatric symptoms include excessive worrying, nervousness, restlessness, inability to relax, and fear of worst-case scenarios
  • Associated physical signs and symptoms include tachycardia, dyspepsia, tremor, dizziness, hyperhidrosis, and cold extremities
  • Patients with generalized anxiety disorder typically perceive impairments in their physical well-being, social relationships, occupation, and home and family life; they have an increased risk of alcohol and other drug abuse, as well as suicide attempts
  • DSM-5 criteria represent the gold standard for diagnosis r1
  • Cognitive behavioral therapy is the preferred treatment at both initial diagnosis and relapse, along with patient education and recommendations for a healthy lifestyle
  • Pharmacologic treatment typically consists of antidepressant therapy; supplemental medication (eg, antipsychotics) is added for refractory cases, usually under the care of a psychiatrist
  • Benzodiazepines have immediate effect and may be used as short-term treatment; however, avoid routine use
  • Most patients are prone to relapse 6 to 12 years after initial diagnosis,r2 with half in partial remission 5 years after initial diagnosis and treatmentr3

Urgent Action

  • Question all patients regarding active suicidal ideation; if discovered, immediately refer to psychiatrist r4

Pitfalls

  • Generalized anxiety disorder often coexists with major depressive disorder and panic disorder; maintain a high index of suspicion during diagnosis r5
  • Consider possible suicidal ideation in patients presenting with generalized anxiety disorder r6

Terminology

Clinical Clarification

  • Generalized anxiety disorder is a common illness characterized by unfocused worry and anxiety, frequently without an immediate cause, occurring on most days for a duration of 6 months or longer, which may be heightened by situational triggers r1r7
    • Manifests physically as increased muscle tension and autonomic hyperactivity r1
    • Negatively affects patient's psychosocial functioning on a near-daily basis r1

Diagnosis

Clinical Presentation

History

  • Hallmark of generalized anxiety disorder is excessive worrying and apprehensive expectation of a wide range of normal events and activities, such as: r1c1c2c3c4c5c6
    • Work or school responsibilities and interactions
    • Family health and finances
  • Common psychological symptoms related to generalized anxiety disorder include: r8
    • Being nervous and unable to relax, with poor or disturbed sleep r1c7c8c9c10c11c12c13c14
    • Worrying about trivial or minor matters, with no control over worrying
    • Extreme restlessness and inability to concentrate r1c15c16
    • Irritability c17c18
    • Fear of the worst happening and feeling scared in general
    • Feeling that objects are unreal (derealization) or that the self is “not really here” (depersonalization) r7c19c20c21c22
    • Sensation of losing control, “going crazy,” or passing out r7c23c24c25c26
    • Fear of death r7c27c28
  • Muscle tension and fatigability are highly correlated with generalized anxiety disorder r1c29c30c31c32
  • Common physical symptoms related to anxiety include the following, ranked in order of clinical significance: r9
  • Other common physical symptoms include: r1
  • Symptoms are typically more severe in younger adults r1

Physical examination

  • Signs related to general emotional well-being include nervousness, irritability, and heightened vigilance r1
  • Physical signs include: r1

Causes and Risk Factors

Causes

  • Exact cause is unknown c79
    • Onset of pure generalized anxiety disorder is often associated with stress arising from emotional loss and dangerous situations r10c80c81c82
      • Includes loss of a close relative or long-term separation from a partner c83c84
    • Childhood adversity has a 32.4% association with anxiety disorders r11c85

Risk factors and/or associations

Age
  • Increasing prevalence with age, peaking in middle age r1
    • Onset of symptoms after the age of 35 years is suggestive of generalized anxiety disorder r12c86
    • Onset rarely occurs before adolescence; prevalence in the adolescent population is 0.9% in the United States r1c87
    • Prevalence among adults (2.9% in the United States) is 3 times greater than in adolescents r12c88
Sex
Genetics
  • Twin studies have demonstrated that there is a moderate genetic risk of generalized anxiety disorder, estimated to be between 15% and 20%,r4 but may be as high as one-thirdr1c91
Ethnicity/race
  • White populations are more likely to be affected than those of African, Asian, or Hispanic ethnicity r14c92c93c94c95
Other risk factors/associations
  • Self-medication
    • Likely to contribute to increased use of alcohol and other drugs in patients with generalized anxiety disorder
    • Use of alcohol and other drugs to treat symptoms of generalized anxiety disorder is estimated to be present in 35% of patients with this disorder r4
  • Coexisting anxiety disorders r5
    • Social phobia is the most prevalent (16%-59%), followed by phobias of other types (eg, specific places, situations, or objects; 16%-46%) c96c97c98
  • Patients from developed countries r1
    • More likely to experience generalized anxiety disorder c99
  • Behavioral inhibition and neuroticism are associated with generalized anxiety disorder r1c100c101

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is based on patient history and physical examination findings; DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, version 5) criteria must be met for a diagnosis of generalized anxiety disorder r1c102
    • Excessive use of alcohol, caffeine, or other stimulants must be ruled out as a cause of symptoms
  • GAD-7 scaler8 and Beck Anxiety Inventoryr9 are alternative diagnostic tools that have proven efficacy in diagnosis, especially the GAD-7
    • GAD-7 assesses symptoms over the past 2 weeks instead of 6 months (per DSM-5r1) using 7 criteria, operating on the assumption that severe symptoms are typically chronic r8
    • Beck Anxiety Inventory contains 21 items comprising somatic, affective, and cognitive symptoms related specifically to anxiety disorders r9
    • Beck anxiety inventory.Scoring: Sum each column. Then sum the column totals to achieve a grand score.From Zarate R: Clinical improvisation and its effect on anxiety: a multiple single subject design. The Arts in Psychotherapy.48:46-53, 2016, Figure A1.
      Not at allMildly but it didn't bother me muchModerately—it wasn't pleasant at timesSeverely—it bothered me a lot
      Numbness or tingling0123
      Feeling hot0123
      Wobbliness in legs0123
      Unable to relax0123
      Fear of worst happening0123
      Dizzy or lightheaded0123
      Heart pounding/racing0123
      Unsteady0123
      Terrified or afraid0123
      Nervous0123
      Feeling of choking0123
      Hands trembling0123
      Shaky/unsteady0123
      Fear of losing control0123
      Difficulty in breathing0123
      Fear of dying0123
      Scared0123
      Indigestion0123
      Faint/lightheaded0123
      Face flushed0123
      Hot/cold sweats0123
      Column sum
    • GAD-7 scale.Scoring: Sum each column. Then sum the column totals to achieve a grand score. The GAD-2 subscale is composed of the first 2 items of the GAD-7 scale.From Wild B et al: Assessing generalized anxiety disorder in elderly people using the GAD-7 and GAD-2 scales: results of a validation study. Am J Geriatr Psychiatry. 22(10):1029-38, Figure 1.
      Over the last 2 weeks, how often have you been bothered by the following problems?Not at allSeveral daysMore than half the daysNearly every day
      Feeling nervous, anxious, or on edge123
      Not being able to stop or control worrying0123
      Worrying too much about different things0123
      Trouble relaxing0123
      Being so restless that it is hard to sit still0123
      Becoming easily annoyed or irritable0123
      Feeling afraid as if something awful might happen0123
      Total score
  • Comprehensive clinical interview is used to assess for the following DSM-5 criteria: r1
    • Excessive anxiety and worry (apprehensive expectation) about various events or activities, such as work or school performance, occurring more days than not, lasting 6 months or longer
    • Patient has difficulty controlling this worry
    • Anxiety and worry occur in conjunction with at least 3 (only 1 required in children) of the following symptoms, with at least some symptoms having been present for more days than not for the past 6 months:
      • Restlessness
      • Fatigability
      • Compromised ability to concentrate
      • Crankiness/irritability
      • Increased muscle tension
      • Poor sleep quality, including trouble falling asleep, difficulty staying asleep, or restlessness
    • Patient's symptoms lead to clinical distress and engender negative effects on work, school, or everyday life
    • Another medical condition or substance use disorder is not the cause
    • Different mental disorder has not given rise to the patient's symptoms
  • Maintain a high index of suspicion for medical conditions that could cause the symptoms; laboratory testing is generally deferred, but CBC, thyroid function tests, basic chemistry panel, urine drug screening, and ECG should be obtained as indicated by the clinical presentation and medical history r15

Functional testing

  • GAD-7 r8c103
    • Consists of 7 criteria, namely:
      • Feeling nervous, anxious, or on edge
      • Not being able to stop or control worrying
      • Worrying too much about different things
      • Trouble relaxing
      • Being so restless that it is hard to sit still
      • Becoming easily annoyed or irritable
      • Feeling afraid as if something awful might happen
    • Subjects rate how often they have been bothered by each symptom in the last 2 weeks, with responses being 0 (not at all), 1 (several days), 2 (more than half the days), and 3 (nearly every day); total score ranges from 0 to 21
      • Threshold score of 8 maximizes sensitivity and 15 maximizes specificity r8
      • Threshold of 10 is optimal for high sensitivity and specificity r8
    • Interpretation r16
      • 10: moderate anxiety
      • 15: indicates severe anxiety
  • Beck Anxiety Inventory r9c104
    • Comprises 21 criteria, specifically:
      • Numbness or tingling
      • Feeling hot
      • Wobbliness in legs
      • Unable to relax
      • Fear of the worst happening
      • Dizzy or lightheaded
      • Heart pounding or racing
      • Unsteady
      • Terrified
      • Nervous
      • Feelings of choking
      • Hands trembling
      • Shaky
      • Fear of losing control
      • Difficulty breathing
      • Fear of dying
      • Scared
      • Indigestion or discomfort in abdomen
      • Faint
      • Face flushed
      • Sweating (not due to heat)
    • Subjects are asked to rate how much each symptom has affected them over the past week on a 4-point scale ranging from 0 (not at all) to 3 (severely—I could barely stand it); total score ranges from 0 to 63
    • Interpretation r17
      • 0 to 9: normal
      • 10 to 18: mild to moderate anxiety
      • 19 to 29: moderate to severe anxiety
      • 30 to 63: severe anxiety

Procedures c105c106

Differential Diagnosis

Most common

  • Anxiety due to thyroid disorder c107c108c109
    • Characterized by unusually highr18 or lowr19 levels of thyroxine due to dysfunction or removal of thyroid gland
    • Anxiety and/or depression symptoms (eg, being more irritable, sad, emotionally sensitive, or anxious) r20
    • Differentiating features are as follows: r21
      • Hypothyroidism can also present with fatigue, dry skin, constipation, vocal changes, and prolonged ankle jerk reflex r21
      • Hyperthyroidism can also present with hypertension, tachycardia, warm and moist skin, and brisk ankle jerk reflex r18
    • DSM-5 diagnostic criteria:
      • Evidence from history, physical examination, or laboratory findings that disturbance is a direct pathophysiologic consequence of another medical condition
      • Disturbance is not better explained by another mental disorder
      • Disturbance does not occur exclusively during the course of a delirium
      • Disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning
    • Diagnosis can be confirmed by the following laboratory findings:
      • Hypothyroidism d1
        • TSH level is elevated to more than 10 mIU/L in primary hypothyroidism r19r22
        • Low serum levels of total or free thyroxine r20
      • Hyperthyroidism d2
        • TSH level is suppressed r18
        • High serum levels of total or free thyroxine
  • Illness anxiety disorder r23r24c110d3
    • Preoccupation with the possibility of having or acquiring serious illness based on misinterpretations of benign or minor physical sensations; previously known as hypochondriasis
    • Some psychological and physical symptoms of anxiety are also present
    • Subject of anxiety differs, as the patient focuses mainly on their body and general health to the exclusion of work, finances, or family matters
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Preoccupation with having or acquiring a serious illness for at least 6 months
      • Frequent visits to the clinic or maladaptive avoidance
  • Social anxiety disorder (social phobia) r25r26c111
    • Phobic anxiety disorder with concerns about social situations involving unfamiliar people or possible scrutiny
    • Psychological and physical symptoms of anxiety are present in certain social situations
    • Anxiety is specific to social situations
      • Characterized by early onset; typically appears by age 11 years in 50% of patients and age 20 years in 80% of patients r26
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Extreme fear or anxiety related to meeting strangers, speaking in public, or being observed in social situations
      • Social phobia must last for at least 6 months and cause clinically significant impairment in social interactions
  • Panic disorder r27c112
    • Marked by recurrent panic attacks or extreme but brief episodes of anxiety, at intervals ranging from 24 hours to several months; may coexist with generalized anxiety disorder
    • Physical signs and symptoms of anxiety (eg, sweating, palpitations, dizziness, tachycardia) are present during a panic attack
    • Intense fear or discomfort of an attack reaches its peak within minutes, unlike the constantly elevated anxiety of generalized anxiety disorder
      • History of childhood trauma or abuse is more likely in patients with panic disorder than in those with generalized anxiety disorder
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Extreme panic or anxiety reaching its peak within minutes, manifesting more than 4 somatic symptoms of anxiety
      • At least 1 panic attack preceded by more than 1 month of apprehensive expectation of a similar episode
  • Major depressive disorder r28r29c113d4
    • Sadness, lethargy, and apathy lasting at least 2 weeks, with reduced interest and pleasure in normal activities; may coexist with generalized anxiety disorder
    • Irritability, fatigue, poor sleep, and digestive symptoms are typically present, as with generalized anxiety disorder
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Depressed mood for most days over 2 weeks along with at least 2 characteristic symptoms
        • Anhedonia
        • Weight loss or gain (unintentional)
        • Insomnia or hypersomnia
        • Psychomotor agitation or retardation
        • Fatigue
        • Feelings of worthlessness or inappropriate guilt
        • Diminished ability to concentrate or indecisiveness
        • Suicidal ideation or attempt
  • Obsessive-compulsive disorder r30c114
    • Characterized by continually recurring thoughts or images (obsessions) that increase anxiety and repetitive or ritualistic actions (compulsions) performed to alleviate that anxiety
    • Excessive worrying and some symptoms of anxiety can be present
    • Differentiated by repetitive rituals and behaviors (eg, hand-washing, mental acts of ordering or checking) performed to alleviate anxiety
      • Anxiety relates more to imagined or fantastic events
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Obsessive thoughts and compulsive behaviors take up at least 1 hour of the day
      • Patient suffers from clinically significant impairment in an occupational or social setting
  • Posttraumatic stress disorder r31c115d5
    • Psychological disturbance or anhedonic/dysphoric mental state caused by experiencing a serious traumatic event
    • Heightened anxiety is typically present, along with its mental and physical symptoms
    • Main distinguishing criterion is the association of anxiety with a specific event, not with normal daily functioning, and the presence of flashbacks, dreams, and dissociative states relating to that event
    • Diagnosis can be confirmed by DSM-5 criteria:
      • Adults and children older than 6 years
        • Traumatic experience (eg, grave injury, sexual violence, threat of death) or such an event affecting a close friend or relative
          • Repeated exposure to circumstances surrounding such events, as with first responders or emergency department personnel
        • Psychological disturbance lasting longer than 1 month, including invasive memories, dreams, flashbacks, avoidance of stimuli associated with such events, irritability, anxiety, and insomnia
        • Patient suffers from clinically significant impairment in an occupational or social setting
      • Children younger than 6 years, specific criteria include:
        • Witnessing traumatic events, especially those affecting a primary caregiver
        • Constriction of play, social withdrawal, and emphasis on expression of negative emotions such as fear, guilt, and shame
  • Drug withdrawal r32c116d6
    • Withdrawal symptoms caused by cessation of sedative use (eg, alcohol, benzodiazepines) or opioid use d7
      • Initial symptoms and signs of withdrawal include heightened anxiety, as well as irritability, nausea, agitation, diaphoresis, and tachycardia from sedative or opioid use
    • Short-term episodic nature of anxiety symptoms, compared to the chronic nature of generalized anxiety disorder symptoms
      • In case of withdrawal from benzodiazepines, signs and symptoms begin 2 to 10 days after last use r32
      • Alcohol withdrawal may be accompanied by seizures and delirium; symptoms typically peak 72 hours after the last ingestion of alcohol (without medication) r32
      • Opioid withdrawal is associated with anxiety and panic symptoms, with onset typically 4 to 6 hours after last use of a shorter-acting opioid (eg, heroin, oxycodone) or 1 to 2 days after last use of an opioid with a longer half-life (eg, methadone, buprenorphine) r33
    • Diagnosis can be confirmed by patient history and observation
  • Substance intoxication r1c117
    • Anxiety and panic may be present with intoxication from a variety of substances, such as stimulants (including caffeine), alcohol, inhalants, cannabis, and phencyclidine
    • Typical history would relate anxiety to intoxication with these substances, which would typically be absent with abstinence
    • Diagnosis primarily made from patient history and clinical signs

Treatment

Goals

  • Alleviate anxiety in the short term and support normal day-to-day functioning
  • Improve quality of life and prevent relapse in the long term

Disposition

Admission criteria

  • Admit patients reporting acute suicidal ideation or intent
  • Consider admission in patients with comorbid conditions (eg, significant substance use disorder with toxicity or withdrawal of sedative-hypnotics [including alcohol])

Recommendations for specialist referral

  • Refer patients to a psychiatrist, psychologist, or appropriately trained mental health therapist for psychotherapy
  • Psychiatric referral is necessary for patients with suicidal ideation or complex coexisting illnesses
  • Psychiatric evaluation, if not already accomplished, is recommended after 2 failed medication trials (ie, 2 different drugs with no response despite reaching target dose) r12

Treatment Options

Owing to the chronicity of generalized anxiety disorder, long-term therapy is anticipated r1

  • Includes psychotherapy, drug therapy, and patient education (eg, self-help Internet sites) regarding disease and healthy lifestyle recommendations
  • Duration of treatment should be at least 12 months to reduce risk of relapse r34

Psychotherapy is often recommended over drug treatment as initial therapy for generalized anxiety disorder because relapse is common after therapeutic medications are withdrawn, lasting beyond the period of withdrawal symptoms after their discontinuation r7

  • Cognitive behavioral therapy is the treatment of choice, with proven efficacy in reducing anxiety symptoms in the short term r35r36r37
    • Best choice of treatment at diagnosis, at 6-month follow-up, and for relapse r7
    • Group format may be preferred treatment in children and adolescents r38
  • Pharmacologic treatment may be given in conjunction with psychotherapy r4

However, drug treatment is commonly prescribed in the primary care setting in the United States because of better resource availabilityr7 and patient preferencer15

  • Antidepressants (selective serotonin reuptake inhibitors such as paroxetine, escitalopram, and sertraline; serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine) are considered first line agents for adults and children r34
    • Fewer adverse effects and lower risk of long-term dependence
    • Take up to 4 weeks to act but significant improvement may be noted in as little as 2 weeks r7r35
    • Withdrawal effects may occur after drug regimen is complete; gradual dose tapering is recommended
  • Second line agents in adults include buspirone, second-generation antipsychotics (eg, quetiapine), benzodiazepines, and anticonvulsants (eg, pregabalin) r34
    • Buspirone typically acts within 72 hours, followed by a mild dysphoric adverse effect; does not lead to dependence r7
      • Do not use as monotherapy when depression is concurrent with anxiety r12
    • Benzodiazepines (eg, diazepam, lorazepam) alleviate anxiety symptoms in the short term, and have a noticeable effect in 15 to 60 minutes, although they are associated with a greater risk of dependence after long-term use r7
      • Not recommended routinely owing to potential for misuse; if used, short-term use (3-6 months) is recommended r34r39
      • More likely to lead to requests for long-term prescription than antidepressants
      • Stronger anxiolytic effect in the first 2 weeks of drug treatment r7
      • May be used initially in combination with an antidepressant (eg, selective serotonin reuptake inhibitor), tapering off after several (4-5) weeks as the antidepressant becomes effective at reducing anxiety; benzodiazepine taper takes 2 to 4 weeks r7
    • A tricyclic antidepressant (eg, imipramine) may be chosen when sedation is a desired effect to mitigate extreme insomnia and restlessness
      • Typically, reserved for those patients with generalized anxiety disorder not responsive to selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors
  • In refractory cases that do not significantly improve with first line drugs augmentation with other drugs has demonstrated some success r7
    • Drugs used in combination with antidepressants have included olanzapine,r40risperidone,r7trifluoperazine, and pregabalinr41
    • Augmentation is typically initiated by a psychiatrist
    • However, a systematic review of augmentation reported a small reduction in symptom severity, with no difference between medication and placebo on functional impairment r42

Drug therapy

  • Selective serotonin reuptake inhibitors c118
    • Escitalopram r7c119
      • Escitalopram Oral tablet; Adults: The initial and recommended dose is 10 mg PO once daily. If clinically indicated, may increase to 20 mg/day after a minimum of 1 week. Periodically reassess the need for continued therapy.
      • Escitalopram Oral tablet; Geriatric Adults: The initial and recommended dose is 10 mg/day PO. Periodically reassess the need for continued therapy.
    • Paroxetine c120
      • Paroxetine Hydrochloride Oral tablet; Adults: 20 mg PO once daily initially, usually in the morning. May titrate by 10 mg/day at weekly intervals if needed and tolerated. Usual effective dose: 20 mg PO once daily. Max: 50 mg/day PO. DEBILITATED or GERIATRIC ADULTS: 10 mg PO once daily initially, may titrate by 10 mg/day at weekly intervals if needed; Max: 40 mg/day PO.
    • Fluoxetine c121
      • Fluoxetine Hydrochloride Oral tablet [Depression/Mood Disorders]; Adolescents and Children 7 years and older: Limited data; not FDA-approved. 10 mg/day PO initially, followed by titration. Limited data suggest that 20 mg/day PO may be an effective dose. Further study is needed.
    • Sertraline c122
      • Sertraline Hydrochloride Oral tablet; Children and Adolescents 7 years and older: 25 mg PO once daily, initially. After 1 week, increase the dose to 50 mg PO once daily. If necessary, increase at intervals of not less than 1 week. Max: 200 mg/day PO. Evaluation of the long-term safety and efficacy of sertraline in the treatment of childhood GAD is needed.
      • Sertraline Hydrochloride Oral tablet; Adults: 25 mg PO once daily initially. After 1 week, increase to 50 mg PO once daily. If necessary, increase by 50 mg/day at intervals of not less than 1 week. Max: 200 mg/day.
  • Serotonin-norepinephrine reuptake inhibitors c123
    • Venlafaxine r7c124
      • Venlafaxine Hydrochloride Oral tablet, extended-release; Children† and Adolescents† 6 years and older: Data are limited. Two placebo-controlled trials 793 pediatric patients with GAD have been conducted with venlafaxine XR, and the data were not sufficient to support a claim for use in pediatric patients, although 1 study did meet the primary endpoint in favor of venlafaxine XR vs. placebo to a statistically significant degree. Dosage was initiated at 37.5 mg PO once daily, and dose titration was determined by weight. For patients 25 to 33 kg, dosage was titrated to a maximum of 112.5 mg/day or a lower maximum tolerated dose. For patients 34 to 49 kg, dosage was titrated to a maximum of 150 mg/day or a lower maximum tolerated dose. Finally, for patients 50 kg or more, the maximum dosage for titration was 225 mg/day PO. As with other antidepressants, the authors recommend close clinical monitoring for adverse events in pediatric patients, including treatment-emergent suicidality.
      • Venlafaxine Hydrochloride Oral tablet, extended-release; Adults: Initially, 75 mg PO once daily. Alternatively, 37.5 mg PO once daily can be given for 4 to 7 days to allow for tolerability before increasing to 75 mg PO once daily. If needed, may increase further by 75 mg/day at intervals of no less than every 4 days. Max: 225 mg PO once daily.
    • Duloxetine c125
      • Duloxetine Oral capsule, gastro-resistant pellets; Children and Adolescents 7 years and older: 30 mg PO once daily for 2 weeks, initially. Then, may consider an increase to 60 mg PO once daily. Recommended range: 30 to 60 mg/day PO. Some patients may benefit from more than 60 mg/day. Increases above 60 mg/day should occur in increments of 30 mg/day. Max: 120 mg/day PO.
      • Duloxetine Oral capsule, gastro-resistant pellets; Adults: 60 mg PO once daily, initially. Alternatively, give 30 mg PO once daily for 1 week before increasing to 60 mg/day PO. Maintenance treatment range: 60 to 120 mg once daily. For dose increases above 60 mg/day, increase in increments of 30 mg/day. Max: 120 mg/day.
      • Duloxetine Oral capsule, gastro-resistant pellets; Geriatric Adults: 30 mg PO once daily for 2 weeks before considering an increase to the target dose of 60 mg once daily. Some patients may benefit from doses above 60 mg/day. For dose increases above 60 mg/day, increase in increments of 30 mg/day. Max: 120 mg/day PO.
  • Benzodiazepines r7c126
    • Diazepam c127
      • Diazepam Oral solution; Infants 6 months and older, Children, and Adolescents: Initially, 1 to 2.5 mg PO 3 to 4 times per day. The dose may be increased as needed and tolerated.
      • Diazepam Oral tablet; Adults: 2 to 10 mg PO 2 to 4 times per day depending upon the severity of the symptoms. Use lower initial adult doses for the debilitated adult patient. Maximum daily dosage has not been defined, but commonly implied limit is 40 mg/day in divided doses for ambulatory use.
      • Diazepam Oral tablet; Geriatric Adults: 2 to 2.5 mg PO 1 to 2 times per day, increasing the dose according to response and patient tolerability. A maximum daily dosage has not been defined, but commonly the adult limits are 40 mg/day in divided doses for ambulatory use. Do not exceed federal Omnibus Budget Reconciliation Act (OBRA) dose of 5 mg/day in residents of skilled nursing facilities without documentation of necessity.
    • Lorazepam c128
      • Lorazepam Oral solution; Adults: Initially, 2 to 3 mg/day PO given in 2 to 3 divided doses. In debilitated adults give 1 to 2 mg/day PO in 2 to 3 divided doses initially. Increase gradually as needed and tolerated. Usual dosage: 2 to 6 mg/day PO. Range: 1 to 10 mg/day PO. When a higher dosage is needed, the evening dose should be increased before the daytime doses.
      • Lorazepam Oral solution; Geriatric Adults: Initially, 1 to 2 mg/day PO given in 2 to 3 divided doses, then increase gradually as needed and tolerated. The usual dosage is 2 to 6 mg/day PO. Use smallest effective dose in order to reduce the risk of ataxia or oversedation. Do not exceed federal Omnibus Budget Reconciliation Act (OBRA) dose of 2 mg/day PO in residents of skilled nursing facilities without documentation of necessity.
    • Alprazolam c129
      • Alprazolam Oral tablet; Adults: 0.25 mg to 0.5 mg PO 3 times daily. Increase doses at 3 to 4 day intervals. Max: 4 mg/day. When discontinuing, decrease daily dose by no more than 0.5 mg every 3 days.
      • Alprazolam Oral tablet; Geriatric Adults: Initially, 0.25 mg PO 2 or 3 times daily. Lower initial doses may be appropriate in some patients. If needed, increase dose gradually. Max: 4 mg/day. Do not exceed the federal Omnibus Budget Reconciliation Act (OBRA) dose of 0.75 mg/day PO in residents of skilled nursing facilities without documentation of necessity. To discontinue, decrease daily dose by no more than 0.5 mg every 3 days.
  • Azapirones c130
    • Buspirone r43c131
      • Buspirone Hydrochloride Oral tablet; Children† and Adolescents† 6 years and older:  Effectiveness has not been established. The safety and effectiveness of buspirone in pediatric patients 6 to 17 years of age (n= 559) were evaluated in 2 placebo-controlled 6-week trials. There was no significant efficacy difference between buspirone and placebo. Long-term safety and efficacy data are lacking.  Dosages studied: 2.5 mg to 5 mg PO twice daily, initially. Increase by 5 mg/day at intervals of 3 to 7 days as needed and tolerated. Max: 60 mg/day, given in 2 to 3 divided doses. In one study of pediatric patients with an anxiety disorder, doses of 5 to 7.5 mg PO twice a day were safe and well-tolerated in children (n = 13) and doses of 5 to 30 mg PO twice daily were found to be safe and tolerated in adolescents (n = 12). The study indicated that children 12 years of age and younger may have a decreased tolerability to high dosages.
      • Buspirone Hydrochloride Oral tablet; Adults: 7.5 mg PO twice daily initially, then increase if needed by 5 mg/day every 2 to 3 days. Usual maintenance dose: 15 to 30 mg/day given in 2 to 3 divided doses. Max: 60 mg/day PO.
      • Buspirone Hydrochloride Oral tablet; Geriatric Adults: 5 mg PO twice daily initially, then increase as needed by 5 mg/day every 2 to 3 days. Usual maintenance dose: 15 to 30 mg/day given in 2 to 3 divided doses. Max: 60 mg/day.
  • Tricyclic antidepressants c132
    • Imipramine r7c133
      • Imipramine Hydrochloride Oral tablet; Adults: Initially, 10 mg PO once daily at bedtime. Titrate by 10 mg PO every 2 to 4 days as tolerated. Average target range is 50 to 200 mg/day. Max: 300 mg/day. r4

Nondrug and supportive care

  • All patients and their family are directed to self-help Internet sites for education on generalized anxiety disorder (eg, Anxiety and Depression Association of Americar45) r44c134
    • Educate patients on lifestyle changes that may help reduce symptoms
      • Improving quality and quantity of sleep c135
      • Regular exercise c136
        • Exercise has been shown to have significant ability to reduce anxiety symptoms and is encouraged r46r47
      • Minimizing caffeine and alcohol intake c137c138
      • Avoiding nicotine and other drugs c139c140
  • Psychotherapy
    • Cognitive behavioral therapy c141
      • Multiple types of psychotherapy have been applied to the treatment of generalized anxiety disorder, with evidence strongest for the efficacy of cognitive behavioral therapy r4
      • Recommended for all patients, although use may be guided by resource availability, patient finances, or patient preference
      • Teaches patients to substitute positive thoughts for anxiety-provoking ones r7
      • Brief description: r48
        • Present a cognitive model of anxiety to the patient and train in self-monitoring and identification of cues that contribute to interpretations of threat
        • Inform patients that therapy focuses on learning different, less anxiety-provoking ways of viewing the self, the world, and the future
        • Use standard cognitive therapy procedures, such as outlining cognitive predictions, interpretations, beliefs, and assumptions that lead to threatening perceptions; emphasize Socratic method (ie, stimulate critical thinking by asking and answering questions)
        • Focus discussions on multiple alternative perspectives for any given situation of daily living; homework emphasizes frequent applications of alternative perspectives and behavioral tasks
      • Reduction in intolerance of uncertainty is an important predictor of outcome
      • Therapy can be delivered in 6 to 12 sessions at weekly intervals r48

Comorbidities

  • Major depressive disorder is the most common coexisting psychiatric illness in patients with generalized anxiety disorder, coexisting in nearly two-thirds of cases r12c142c143
    • Occurs more often in women than in men r1
    • Combination of these disorders is termed cothymiar7
    • Antidepressants are the preferred drug treatment, in combination with cognitive behavioral therapy
  • Panic disorder r7c144
    • Occurs in 25% to 50% of patients with generalized anxiety disorder r5r12
    • Combination of buspirone with cognitive behavioral therapy is more effective than psychotherapy alone

Special populations

  • Children
    • Preferably, treat with cognitive behavioral therapy; medications such as antidepressants are often avoided over concern for adverse effects r7
      • However, the combination of cognitive behavioral therapy and sertraline has demonstrated efficacy in children between the ages of 7 and 17 years r49
  • Pregnant patients
    • In the perinatal period, generalized anxiety may be exacerbated, requiring pharmacotherapy in addition to psychotherapy r12
      • Prescribe half the usual drug dose (typically buspirone) for pregnant patients, as benzodiazepines may have teratogenic effects r12
      • 1 of the goals of therapy in these patients is to prevent premature birth or miscarriage due to anxiety

Monitoring

  • When initiating drug therapy, see patients every 2 to 4 weeks; frequency is decreased to every 3 to 4 months during maintenance therapy r12
    • If medication is effective, continue course for 6 to 12 months and then slowly taper off r3
  • After taper, 6-month follow-up is necessary r7
    • Optional continued follow-up every 6 months for a period of 5 years or longer is recommended since rates of relapse are high r3

Complications and Prognosis

Complications

  • Generalized anxiety disorder affects quality of life r50c145
    • Patients with anxiety disorders perceive impairments in their physical well-being, social relationships, occupation, and home and family life
  • If untreated, generalized anxiety disorder can lead to alcohol and other drug abuse, as patient self-medicates to control symptoms c146c147
  • Patients have increased odds of 2.32 for suicidal ideation and an odds ratio of 3.64 for suicide attempts, as demonstrated by longitudinal analysis r6c148c149

Prognosis

  • Most patients are susceptible to a relapse of generalized anxiety disorder 6 to 12 years after initial diagnosis r2
    • Patients who improve the most initially also have the best long-term outcome r7
  • Rate of full remission is 27% at 3 years and 38% at 5 years postdiagnosis r3
  • Rates of partial remission are 37% at 3 years and 47% at 5 years postdiagnosis r3

Screening and Prevention

Screening c150

Screening tests

  • Women's Preventive Services Initiative guidelines recommend screening for anxiety in women and adolescent girls aged 13 years or older, including pregnant and postpartum patients r51r52
    • Use clinical judgment to determine frequency of screening
  • Appropriate screening instruments include: r51r53
    • Beck Anxiety Inventory
    • GAD-7 (Generalized Anxiety Disorder Scale)
    • K-10 (Kessler Psychological Distress Scale)
    • PHQ-9 (Patient Health Questionnaire)
    • GAD-2, PHQ-2, K-6 (abbreviated versions of the above scales)
    • SCARES (Screen for Child Anxiety Related Emotional disorders Scale)
    • HADS (Hospital Anxiety and Depression Scale)
    • Edinburgh Postnatal Depression Scale
    • Bright Futures Pediatric Symptom Checklist–Youth Report in adolescents and young women

Prevention c151

American Psychiatric Association: Generalized anxiety disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:222-6Tyrer P et al: The Nottingham Study of Neurotic Disorder: predictors of 12-year outcome of dysthymic, panic and generalized anxiety disorder. Psychol Med. 34(8):1385-94, 200415724870Yonkers KA et al: Factors predicting the clinical course of generalised anxiety disorder. Br J Psychiatry. 176:544-9, 200010974960Stein MB et al: Clinical practice. Generalized anxiety disorder. N Engl J Med. 373(21):2059-68, 201526580998Noyes R Jr: Comorbidity in generalized anxiety disorder. Psychiatr Clin North Am. 24(1):41-55, 200111225508Sareen J et al: Anxiety disorders and risk for suicidal ideation and suicide attempts: a population-based longitudinal study of adults. Arch Gen Psychiatry. 62(11):1249-57, 200516275812Tyrer P et al: Generalised anxiety disorder. Lancet. 368(9553):2156-66, 200617174708Spitzer RL et al: A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med. 166(10):1092-7, 200616717171Beck AT et al: An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 56(6):893-7, 19883204199Kendler KS et al: Life event dimensions of loss, humiliation, entrapment, and danger in the prediction of onsets of major depression and generalized anxiety. Arch Gen Psychiatry. 60(8):789-96, 200312912762Green JG et al: Childhood adversities and adult psychiatric disorders in the national comorbidity survey replication I: associations with first onset of DSM-IV disorders. Arch Gen Psychiatry. 67(2):113-23, 201020124111Fricchione G: Clinical practice. Generalized anxiety disorder. N Engl J Med. 351(7):675-82, 200415306669Vesga-López O et al: Gender differences in generalized anxiety disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). J Clin Psychiatry. 69(10):1606-16, 200819192444Lewis-Fernández R et al: Culture and the anxiety disorders: recommendations for DSM-V. Depress Anxiety. 27(2):212-29, 201020037918Patel G et al: In the clinic. Generalized anxiety disorder. Ann Intern Med. 159(11):ITC6-1, ITC6-2, ITC6-3, ITC6-4, ITC6-5, ITC6-6, ITC6-7, ITC6-8, ITC6-9, ITC6-10, ITC6-11; quiz ITC6-12, 201324297210Löwe B et al: Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population. Med Care. 46(3):266-74, 200818388841Julian LJ: Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Arthritis Care Res (Hoboken). 63 Suppl 11:S467-72, 201122588767Devereaux D et al: Hyperthyroidism and thyrotoxicosis. Emerg Med Clin North Am. 32(2):277-92, 201424766932Garber JR et al: Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 22(12):1200-35, 201222954017Constant EL et al: Anxiety and depression, attention, and executive functions in hypothyroidism. J Int Neuropsychol Soc. 11(5):535-44, 200516212680Almandoz JP et al: Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am. 96(2):203-21, 201222443971Jonklaas J et al: Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid. 24(12):1670-751, 201425266247Olatunji BO et al: Is hypochondriasis an anxiety disorder? Br J Psychiatry. 194(6):481-2, 200919478284American Psychiatric Association: Illness anxiety disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:315-8American Psychiatric Association: Social anxiety disorder (social phobia). In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:202-8Stein MB et al: Social anxiety disorder. Lancet. 371(9618):1115-25, 200818374843American Psychiatric Association: Panic disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:208-14Belmaker RH et al: Major depressive disorder. N Engl J Med. 358(1):55-68, 200818172175American Psychiatric Association: Major depressive disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:160-8American Psychiatric Association: Obsessive-compulsive disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:237-42American Psychiatric Association: Posttraumatic stress disorder. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:271-80Kosten TR et al: Management of drug and alcohol withdrawal. N Engl J Med. 348(18):1786-95, 200312724485Sharma B et al: Opioid use disorders. Child Adolesc Psychiatr Clin N Am. 25(3):473-87, 201627338968Strawn JR et al: Pharmacotherapy for generalized anxiety disorder in adult and pediatric patients: an evidence-based treatment review. Expert Opin Pharmacother. 19(10):1057-70, 201830056792DeMartini J et al: Generalized anxiety disorder. Ann Intern Med. 170(7):ITC49-ITC64, 201930934083Hunot V et al: Psychological therapies for generalised anxiety disorder. Cochrane Database Syst Rev. CD001848, 200717253466Schwartz C et al: Six decades of preventing and treating childhood anxiety disorders: a systematic review and meta-analysis to inform policy and practice. Evid Based Ment Health. 22(3):103-10, 201931315926Zhou X et al: Different types and acceptability of psychotherapies for acute anxiety disorders in children and adolescents: a network meta-analysis. JAMA Psychiatry. 76(1):41-50, 201930383099Bandelow B: Current and novel psychopharmacological drugs for anxiety disorders. Adv Exp Med Biol. 1191:347-65, 202032002937Pollack MH et al: Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study. Biol Psychiatry. 59(3):211-5, 200616139813Hidalgo RB et al: Generalized anxiety disorder. Handb Clin Neurol. 106:343-62, 201222608630Patterson B et al: Augmentation strategies for treatment-resistant anxiety disorders: a systematic review and meta-analysis. Depress Anxiety. 33(8):728-36, 201627175543Chessick CA et al: Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. CD006115, 200616856115National Institute for Health and Care Excellence: Generalised Anxiety Disorder and Panic Disorder in Adults: Management. Clinical guideline CG113. NICE website. Updated July 26, 2019. Accessed December 10, 2020. https://www.nice.org.uk/guidance/cg113https://www.nice.org.uk/guidance/cg113Anxiety and Depression Association of America. ADAA website. Accessed December 10, 2020. https://www.adaa.org/https://www.adaa.org/Bourbeau K et al: The combined effect of exercise and behavioral therapy for depression and anxiety: systematic review and meta-analysis. Behav Sci (Basel). 10(7), 202032674359Stubbs B et al: An examination of the anxiolytic effects of exercise for people with anxiety and stress-related disorders: a meta-analysis. Psychiatry Res. 249:102-8, 201728088704Borkovec TD et al: A component analysis of cognitive-behavioral therapy for generalized anxiety disorder and the role of interpersonal problems. J Consult Clin Psychol. 70(2):288-98, 200211952187Walkup JT et al: Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 359(26):2753-66, 200818974308Olatunji BO et al: Quality of life in the anxiety disorders: a meta-analytic review. Clin Psychol Rev. 27(5):572-81, 200717343963Gregory KD et al: Screening for anxiety in adolescent and adult women: a recommendation from the Women's Preventive Services Initiative. Ann Intern Med. 173(1):48-56, 202032510990Nelson HD et al: Screening for anxiety in adolescent and adult women: a systematic review for the Women's Preventive Services Initiative. Ann Intern Med. 173(1):29-41, 202032510989Staples LG et al: Psychometric properties and clinical utility of brief measures of depression, anxiety, and general distress: The PHQ-2, GAD-2, and K-6. Gen Hosp Psychiatry. 56:13-18, 201930508772