Endocrine and metabolic disorders: hyperthyroidism, hypoglycemia, Addison disease, Cushing disease,
pheochromocytoma, PMS, electrolyte abnormalities, acute intermittent porphyria, anemia
migraines, myasthenia gravis, Parkinson disease, vertigo, essential tremor
Cardiovascular: mitral valve prolapse, CHF, arrhythmias, post-MI, hyperdynamic β-adrenergic state,
hypertension, angina pectoris, postcerebral infarction
GI: PUD, Crohn disease, ulcerative colitis, irritable bowelsyndrome
Respiratory: COPD, asthma, pneumonia, pulmonary edema, respirator dependence, pulmonary embolus
Others: HIV infection, systemic lupus erythematosus
nicotine (and withdrawal), PCP, phenylephrine, pseudoephedrine
CNS depressant withdrawal: barbiturates, benzodiazepines, ethanol, opiates
Psychotropics: antipsychotics (akathisia), bupropion, buspirone, SNRIs, SSRIs, TCAs
thyroid hormone, triptans, vinblastine, yohimbine
gastrointestinal; HIV, human immunodeficiency virus; MDMA, 3,4-methylenedioxymethamphetamine; MI,
serotonin reuptake inhibitors; TCAs, tricyclic antidepressants.
Symptoms of Generalized Anxiety Disorder
Anxiety and worry are associated with at least three of the following symptoms (or one in children):
Restlessness or feeling keyed up or on edge
Difficulty concentrating or mind going blank
Genetic factors play a significant role in the etiology of GAD. Genes involved in the
hereditary development of GAD are believed to be the same as those for neuroticism
and major depression, with environmental factors determining which disorder is
5,17,18 Biologic studies in GAD have found abnormalities in
noradrenergic, serotonergic, and CCK and GABA-A receptor function.
-adrenergic receptors in GAD patients, and this is
believed to represent downregulation of receptors in response to high catecholamine
Treatment of Generalized Anxiety Disorder
Management of GAD can involve both nonpharmacologic and pharmacologic
therapies. Nondrug treatments such as supportive psychotherapy, dynamic
psychotherapy, cognitive behavioral therapy (including internet or computer based
programs), relaxation training, and meditation are often helpful in relieving anxiety
19–21 Cognitive therapy is aimed at identifying negative
thought patterns provoking or worsening anxiety and making them more positive.
Cognitive behavioral therapy (CBT) has been associated with significant reductions
in anxiety that are maintained for 6 to 12 months, as well as decreased psychiatric
Benzodiazepines are widely prescribed anxiolytic agents, and their efficacy in
treating GAD and other anxiety disorders, particularly in the short term, is well
22 Benzodiazepines offer rapid symptom relief, but are still associated
with risks of dependence and withdrawal and are not recommended for the long-term
Benzodiazepines have four distinct effects: anxiolytic, anticonvulsant, muscle
relaxant, and sedative-hypnotic. Benzodiazepines potentiate GABA by binding to
sites on the central GABA-A receptor which serve as the main inhibitory
23 These agents are used to treat a wide variety of
medical and psychiatric conditions, including muscle spasms, seizures, anxiety
disorders, acute agitation, and insomnia. Benzodiazepines with a rapid onset and
short duration of action are commonly used to decrease anxiety and apprehension, as
well as induce sedation before surgery and other medical procedures.
Clinical Comparison of Benzodiazepine Agents
(Tranxene, TranxeneSD, generic)
Sedative-hypnotic 1–2 mg HS 1 mg HS 2
Sedative-hypnotic 15–30 mg HS 15 mg HS 30
Quazepam (Doral) Sedative-hypnotic 7.5–15 mg HS 7.5 mg HS 15
Sedative-hypnotic 15–30 mg HS 15 mg HS 30
Sedative-hypnotic 0.125–0.25 mg HS 0.125 mg HS 0.25
aCombination product containing amitriptyline.
FDA, US Food and Drug Administration; HS, at bedtime.
Clinical Comparison of Benzodiazepines
Of the 14 benzodiazepines commercially available in the United States, 7 are
marketed as antianxiety agents, 6 as oral sedative-hypnotics., and 1 as an
anticonvulsant. Indications reflect manufacturers’ labeling decisions because
anxiolytics can be effective sedatives and vice versa.
Table 83-4 compares the clinical profiles of marketed oral benzodiazepines.
Midazolam and clobazam are not included in Table 83-4 as these agents are not used
in the treatment of anxiety. Most benzodiazepines have unlabeled uses, including
treatment of anxiety and agitation associated with medical or psychiatric illnesses;
alcohol withdrawal; irritable bowel syndrome; premenstrual syndrome;
chemotherapy-induced nausea and vomiting; catatonia; tetanus; involuntary movement
disorders (restless legs syndrome, akathisia, tardive dyskinesia, essential tremor);
and spasticity associated with various neurologic disorders (cerebral palsy,
Antidepressants are the recommended first-line treatment for most patients with
GAD, though benzodiazepines are widely prescribed. One important distinction
between these two medication classes is that the anxiolytic effects of
benzodiazepines occur almost immediately, whereas the effects of antidepressants
occur gradually over several weeks. Therefore, it is common for short-term
benzodiazepine therapy to be prescribed in combination with an antidepressant
during initial treatment of many anxiety disorders.
As shown in Table 83-5, selective serotonin reuptake inhibitors (SSRIs) have
since gained first-line status for treating all five primary anxiety disorders.
these agents, in addition to serotonin and norepinephrine reuptake inhibitors (SNRIs),
first line is increasingly common when compared to alternatives due to their
tolerability profile as well as utility in treating the common comorbid presentation of
Early controlled studies found trazodone, doxepin, imipramine, and amitriptyline
comparably effective or superior to benzodiazepines in treating GAD.
benzodiazepines work quickly, and TCA treatment is often associated with initial
increases in anxiety (especially with higher dosages), continued TCA therapy is
usually effective if side effects are tolerated. However, TCAs are not widely used
for treating anxiety disorders because attention has turned to other much safer and
better tolerated antidepressants, including SSRIs and SNRIs.
Summary of Comparative Medication Treatment Options for Anxiety Disorders
FDA-Approved FirstLine Treatments (Unless
Otherwise Noted) Second-Line Treatments Possible Alternatives
aNot US Food and Drug Administration (FDA) approved for the indication but evidence supports use
(side effects, potential toxicity, drug interactions).
Paroxetine and escitalopram are SSRIs approved for GAD by the US Food and
Drug Administration (FDA). Sertraline and citalopram have also been studied for
this indication and the former is the preferred first-line agent according to one
24 Overall, SSRIs and SNRIs are recommended for first-line use and
specific agents should be selected based on patient-specific factors (e.g., risk for
discontinuation syndrome, drug interactions, tolerability, and patient preference).
Like TCAs, patients may experience an initial increase in anxiety during SSRI
treatment, so lower-than-normal SSRI starting doses should be used in patients with
GAD, particularly if fluoxetine is utilized, as it may be more likely than other SSRIs
to cause anxiety as an initial side effect.
SNRIs, venlafaxine and duloxetine, are FDA-approved for the treatment of GAD.
Newer SNRIs including levomilnacipran, milnacipran, and venlafaxine’s active
metabolite, desvenlafaxine, have not been well studied in the management of anxiety.
However, data suggest these agents may be useful for the treatment of anxiety
symptoms associated with depression, although further randomized controlled trials
are needed to confirm this finding.
27–29 The side effect profile of venlafaxine and
other SNRIs is similar to that of the SSRIs, with dose-related nausea being the most
common, and this usually subsides after 1 to 2 weeks of continued therapy. Similar to
SSRIs, vigilance for worsening anxiety is required upon initiation of treatment and
low doses should be utilized to mitigate this potential effect. Significant increases in
blood pressure with venlafaxine are not usually seen within the
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