> Table of Contents > Anxiety (Generalized Anxiety Disorder)
Anxiety (Generalized Anxiety Disorder)
Jay A. Brieler, MD
Clarice Nelson, MD
image BASICS
  • Persistent, excessive, and difficult-to-control worry associated with significant symptoms of motor tension, autonomic hyperactivity, and/or disturbances of sleep or concentration.
  • System(s) affected: nervous (resulting in increased sympathetic tone and increased catecholamine release); may have secondary effects on other symptoms such as cardiac (tachycardia) and GI (nausea, irregular bowels)
  • 12-month prevalence rate: 2-3%
  • Lifetime prevalence rate: 5%
  • Onset can occur any time in life but is typically during adulthood; median age of onset in the United States is 31 years.
  • Predominant sex: female > male (2:1) (1)
  • May be mediated by abnormalities of neurotransmitter systems (i.e., serotonin, norepinephrine, and γ-aminobutyric acid [GABA])
  • Associated with altered regional brain function (increased activity in the amygdala and prefrontal cortex) (2)
  • Strongly linked to depression in heritability studies
  • A variant of the serotonin transporter gene (5HT1A) may contribute to both conditions; other genes (such as that for glutamic acid decarboxylase) also may play a role.
  • Caucasian race
  • Adverse life events: stress, medical illness, disability, unemployment, and childhood physical and mental abuse
  • Family history
  • Lack of social support
  • Obesity
  • Comorbid psychiatric disorders (3)
  • Regular exercise is associated with decreased anxiety and depression.
  • CBT and parental intervention in children with social withdrawal or early anxiety may protect against the development of GAD (3).
  • Major depressive disorder (>60%), dysthymia, bipolar disorder
  • Alcohol/drug abuse
  • Cigarette smoking in adolescence
  • Panic disorder, agoraphobia, simple phobia, social anxiety disorder, anorexia nervosa
Useful for identifying other differential diagnosis (see below). No specific physical findings in GAD, but patient may exhibit irritability, bitten nails, tremor, or clammy hands.
  • Cardiovascular: ischemic heart disease, valvular heart disease (mitral valve prolapse), cardiomyopathies, arrhythmias, congestive heart failure
  • Respiratory: asthma, chronic obstructive pulmonary disease, pulmonary embolism
  • CNS: stroke, seizures, dementia, migraine, vestibular dysfunction, neoplasms
  • Metabolic and hormonal: hyper- or hypothyroidism, pheochromocytoma, adrenal insufficiency, Cushing syndrome, hypokalemia, hypoglycemia, hyperparathyroidism
  • Nutritional: thiamine, pyridoxine, or folate deficiency; iron deficiency anemia
  • Drug-induced anxiety: alcohol, sympathomimetics (cocaine, amphetamine, caffeine), corticosteroids, herbals (ginseng)
  • Withdrawal: alcohol, sedative-hypnotics
  • Psychiatric: other disorders (e.g., panic disorder, obsessive-compulsive disorder, PTSD, social phobia, adjustment disorder, and somatization disorder)
Initial Tests (lab, imaging)
  • Laboratory tests are normal. Initial tests may include thyroid-stimulating hormone, CBC, basic metabolic panel, urine drug screen, and ECG.
  • GAD-2: 2-question self-reporting scale (22% positive predictive value [PPV]/78% negative predictive value [NPV])
  • PHQ-4 provides a very brief screen for both anxiety and depression (3).
Diagnostic Procedures/Other
Psychological testing
  • GAD-7: 5 additional questions; provides more detailed information for treatment (29% PPV/71% NPV); also may be indicative of panic disorder (GAD-7: 29% PPV/71% NPV).
  • Hamilton Anxiety Scale (HAM-A), Anxiety Disorders Interview Schedule (ADIS-IV)
  • In pediatric populations: ADIS-IV Parent and Child Version, Multidimensional Anxiety Scale for Children (MASC), Screen for Child Anxiety Related Emotional Disorders (SCARED)
  • Assess for suicidality given increased risk.
  • Identify and treat coexisting substance abuse and other psychiatric conditions.
Psychotherapeutic approaches
  • Psychological treatments are effective in treating GAD: number needed to treat (NNT) = 2 (5)[A].
  • Cognitive-behavioral therapy (CBT): Most well-studied psychological treatment; may improve comorbid conditions such as depression. Treatment of choice when available (3)[A]
  • Relaxation/mindfulness training (3)[A]
  • Psychodynamic psychotherapy: Treatment is focused on patient discovering and verbalizing unconscious conflicts (3)[C].
  • Insufficient evidence to compare efficacy of the various treatment types at this time (5)[A]
First Line
  • SSRI and SNRI antidepressants have demonstrated efficacy, are well-tolerated, do not cause abuse/dependence, and treat comorbid depression. Data to compare between agents are limited (6)[A].
  • SSRIs
    • Paroxetine (Paxil): initially 10 to 20 mg/day; may titrate to a maximum of 50 mg/day (no added benefit more than 20 mg/day)
    • Escitalopram (Lexapro): initially 10 mg/day; may titrate to a maximum of 20 mg/day
    • Sertraline (Zoloft): initially 25 mg/day; may titrate to a maximum of 200 mg/day
    • Fluoxetine (Prozac) and citalopram (Celexa) likely have efficacy for GAD but do not have FDA indications
  • SNRIs
    • Duloxetine (Cymbalta): initially 30 mg/day; may titrate to a maximum of 120 mg/day
    • Venlafaxine XR (Effexor XR): initially 37.5 to 75 mg; may titrate up by 75 mg every 4 days to a maximum of 225 mg/day
Second Line
  • Benzodiazepines (efficacious in the short-term but less effective long-term), risk for dependence (5)[A]
    • Clonazepam (Klonopin): 0.25 mg BID; may increase to 4 mg/day divided BID
    • Diazepam (Valium): 2 to 5 mg BID-QID; may increase to a maximum of 40 mg/day
    • Lorazepam (Ativan): 0.5 mg BID-TID; may increase to 6 mg/day divided TID
    • Alprazolam (Xanax): 0.25mg TID; may increase to 4 mg/day
  • Hydroxyzine (Vistaril, Atarax): CNS depressant, antihistamine, anticholinergic; decreased risk of dependence compared with benzodiazepines: usual dose: 50 to 100 mg PO QID; limit use in the elderly (3)[B]
  • P.69

  • Azapirones: buspirone (BuSpar): less risk of dependence, although may be less effective. 15 mg/day divided BID-TID initially; maximum of 60 mg/day divided BID-TID (6)[A]
  • Quetiapine (Seroquel): optimal dose 150 mg/day. Second-generation antipsychotic. Efficacious but less well-tolerated than SSRIs (6,7)[A].
  • Pregabalin (Lyrica): has shown promise in decreasing anxiety scores and preventing relapse at 75 to 300 mg BID; may cause less sexual dysfunction and sleep disruption than SSRIs (6)[A]
  • Tricyclic antidepressants (TCAs): imipramine (Tofranil): initially 25 to 50 mg/day; maximum of 300 mg/day, 100 mg/day in the elderly
Geriatric Considerations
  • Avoid TCAs and long-acting benzodiazepines; benzodiazepines may cause delirium.
  • Pregabalin may cause dizziness and somnolence.
Pediatric Considerations
  • Black box warning (SSRIs): Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults.
  • However, studies have also shown increase in suicide attempts in adolescents after SSRI discontinuation.
  • Medications other than SSRIs have not been well-tested in pediatric populations.
  • Anxiety and ADHD often co-occur.
Pregnancy Considerations
  • Buspirone: Category B: secreted in breast milk; inadequate studies to assess risk
  • Benzodiazepines: Category D: may cause lethargy and weight loss in nursing infants; avoid breastfeeding if the mother is taking chronically or in high doses
  • SSRIs: if possible, taper and discontinue. After 20 weeks' gestation, there is increased risk of pulmonary hypertension; mild transient neonatal syndrome of CNS; and motor, respiratory, and GI signs. Studies regarding risk of autism show mixed results. Most are Category C:
    • Paroxetine: Category D: conflicting evidence regarding the risk of congenital cardiac defects and other congenital anomalies
    • Hydroxyzine: Category C: Case reports of neonatal withdrawal exist.
  • Benzodiazepines: age >65 years, hepatic insufficiency, respiratory disease/sleep apnea, renal insufficiency, suicidal tendency, contraindicated with narrow-angle glaucoma, precaution with open-angle glaucoma; sudden discontinuation, especially of alprazolam, increases seizure risk. Long-term use has potential for tolerance and dependence; use with caution in patients with history of substance abuse.
  • Buspirone: hepatic and/or renal dysfunction; monoamine oxidase inhibitor (MAOI) treatment
  • TCAs: advanced age, glaucoma, benign prostatic hypertrophy, hyperthyroidism, cardiovascular disease, liver disease, urinary retention, MAOI treatment
  • SSRIs: use caution in those with comorbid bipolar disorder; may trigger mania. Avoid with medications that may increase risk of serotonin syndrome.
Concomitant depression or other comorbidities may warrant a psychiatric evaluation in light of increased suicide risk.
  • Patients frequently engage in complementary and alternative medicine (CAM); providers should be familiar with common therapies.
  • Probable benefit but more study needed on several complementary therapies, including acupuncture, yoga, tai chi, and aromatherapy (8)[A].
  • Kava: Some evidence for benefit over placebo in mild to moderate anxiety, but concern regarding potential hepatotoxicity persists. Safety is potentially affected by many factors, including manufacturing quality, plant part used, dose, and interactions with other substances (8)[A].
  • Limited evidence to support other herbal medicines and St. John's wort likely not effective (8)[A]
  • Strong evidence to support regular physical activity to relieve anxiety symptoms (8)[A]
Patients at risk of suicide should be treated as inpatients; may be considered as well for patients with substantial interference in daily function.
Patient Monitoring
  • Follow up within 2 to 4 weeks from starting new medications.
  • Medications should be continued past the initial period of response and probably for at least 6 months (6)[A].
  • Monitor mental status on benzodiazepines and avoid drug dependence.
  • Monitor BP, heart rate, and anticholinergic side effects of TCAs.
  • Monitor all patients for suicidal ideation but especially those on SSRIs, SNRIs, and imipramine.
  • Limit caffeine intake.
  • Avoid alcohol (drug interactions, high rate of abuse, potential for increased anxiety).
  • Regular exercise, especially yoga, may be beneficial for both anxiety and comorbid conditions.
  • Psychoeducation regarding normal versus pathologic anxiety, the fight or flight response, and the physiology of anxiety can be extremely helpful.
  • Moderate caffeine use; avoid alcohol and nicotine if possible.
  • Probability of recovery is approximately 40-60%, but relapse is common.
  • Comorbid psychiatric disorders and poor relationships with spouse or family make relapse more likely (1).
1. Weisberg RB. Overview of generalized anxiety disorder: epidemiology, presentation, and course. J Clin Psychiatry. 2009;70(Suppl 2):4-9.
2. Hilbert K, Leuken U, Beesdo-Baum K. Neural structures, functioning and connectivity in generalized anxiety disorder and interaction with neuroendocrine systems: a systematic review. J Affect Disord. 2014;158:114-126.
3. Patel G, Fancher TL. In the clinic. Generalized anxiety disorder. Ann Intern Med. 2013;159(11):ITC6-1-ITC6-11.
4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
5. Cuijpers P, Sijbrandij M, Koole S, et al. Psychological treatment of generalized anxiety disorder: a metaanalysis. Clin Psychol Rev. 2014;34(2):130-140.
6. Baldwin DS, Waldman S, Allgulander C. Evidence-based pharmacological treatment of generalized anxiety disorder. Int J Neuropsychopharmacol. 2011;14(5):697-710.
7. Depping AM, Komossa K, Kissling W, et al. Second-generation antipsychotics for anxiety disorders. Cochrane Database Syst Rev. 2010;(12):CD008120.
8. Sarris J, Moylan S, Camfield DA, et al. Complementary medicine, exercise, meditation, diet, and lifestyle modification for anxiety disorders: a review of current evidence. Evid Based Complement Alternat Med. 2012;2012:809653.
See Also
Algorithms: Depressive Episode, Major; Anxiety
  • F41.9 Anxiety disorder, unspecified
  • F41.1 Generalized anxiety disorder
  • F41.8 Other specified anxiety disorders
Clinical Pearls
  • Psychiatric comorbidities, especially depression, are extremely common with GAD; patients are at increased risk for suicidality.
  • CBT and SSRIs (possibly in combination) are the treatments of choice.
  • Starting antidepressant medication at low doses, with careful titration to full therapeutic dosing, helps minimize side effects while maximizing efficacy.
  • Benzodiazepines may be used initially but should be tapered and withdrawn if possible.
  • CAM use is common, and certain therapies may be effective.