Generalized Anxiety Disorder

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Fricchione G.  Generalized Anxiety Disorder.  New England Journal of Medicine 2004; 351 (7):  675-682.
Review by Evan Schwarz, MD

Next to substance abuse, anxiety disorders are some of the most prevalent psychiatric conditions today with generalized anxiety disorder (GAD) having a lifetime prevalence of 5%. This disorder, which is more prevalent among women, often begins before age 25 and has a low rate of remission without treatment. The American Psychiatric Association established a diagnostic criteria for GAD that includes: excessive anxiety/worry occurring more days than not for at least 6 months; difficulty controlling worrying; anxiety/worry that isn’t confined to features of other psychiatric disorders; mental or physical symptoms that cause significant distress or impairment in important areas of function, and symptoms that are not the physiologic effect of a medicine or another organic disease process. Also the anxiety/worry must be associated with at least three of the following six symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance. Patients at risk include those with a family history, increased stress, and previous physical or emotional trauma. GAD has also been associated with heavy smokers and certain medical illnesses such as diabetes.
To make this diagnosis, other medical disorders, drug use (cocaine, amphetamines) or withdrawal, and recent changes in prescribed (corticosteroids) or OTC medicines (ginseng, caffeine) need to be ruled out. There are clues you can spot that suggest that anxiety is a symptom (as opposed to the clinical disorder). These clues include onset after 35, no previous history of anxiety, little change in life stressors, patients do not try to avoid anxiety-provoking situations, and a poor response to pharmacologic therapy. No specific recommendations can be made regarding laboratory evaluation aside from the possible helpfulness of thyroid evaluation as there is a high prevalence of GAD in patients suffering from hyperthyroidism. What also makes this disease difficult to diagnose is that is often occurs alongside other psychiatric conditions. The most common is major depression which occurs in two out of three patients with GAD. Panic disorder (recurrent attacks followed by one month of anxiety over concern of future attacks) and alcohol abuse also have a high incidence in this population.
Once the diagnosis of GAD has been established, there are many therapies to consider. In general the practitioner must remember that many of these therapies take at least 4 weeks to have an effect, are associated with many side effects, require close supervision including increases and weans of the medications, can be associated with abuse and withdrawal (benzodiazepines), and the need to treat concomitant substance abuse. As these treatments can take time to work, one should be cautious about starting them in the ED. TCAs including imipramine and nortriptyline should be started at half the usual dose. These drugs are well known to have many side effects including arrhythmias, tachycardia, orthostasis, weight gain, and anticholinergic effects. Also, they can be lethal in overdose.
SSRIs have become very popular as they are equally as efficacious as TCAs but have less severe side effects. As restlessness can occur with drug initiation, starting doses should be low. Paroxetine does have FDA approval for the treatment of GAD. While the initiation of SSRIs does mandate monitoring for suicidal ideation, current reviews including nearly 50,000 patients did not show an increased rate in placebo-controlled studies. SSRIs include citalopram, escitalopram, paroxetine, and sertraline. Side effects include nausea, vomiting, diarrhea, dry mouth, and sexual dysfunction. Venlafaxine, an SNRI, is a closely related medication that also has FDA approval for GAD. Side effects of this drug include systolic hypertension and conduction defects and ventricular arrhythmias as well as many of the same side effects from SSRIs.
Other options include buspirone, anticonvulsants (gabapentin and tiagabine), and benzodiazepines. Buspirone is a nonbenzodiazepine anxiolytic. While it has several advantages including not causing sedation, physical dependency, or withdrawal, it does not have an antidepressant effect and can take 4 weeks to have a therapeutic effect. While benzodiazepines have been shown to be effective within 2 weeks, they were the least effective medication by 8 weeks and are addictive.
Pregnant or postpartum women deserve special attention as they are at an increased risk. Buspirone may be safe during pregnancy, but benzodiazepines should probably be avoided due to defects in first and third trimesters as well as sedation effects seen in breast feeding. While SSRIs appear not to be teratogenic, there have been reports of neonatal toxicity, early delivery, and respiratory distress with particular concern for paroxetine use near delivery. Use of the lowest effective dose is advised during pregnancy and lactation. 


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