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The new england journal of medicine This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author’s clinical recommendations. During a routine visit, a 59-year-old woman, who describes herself as a lifetime “wor-
rier” and has a family history of depression, reports having restless sleep, muscle ten-
sion, and fatigue. Recently, her anxiety has intensified about her children, her job, and
her health, and it is having a negative effect on her family and work life. How should
she be treated?
Anxiety disorders are the most prevalent psychiatric conditions in the United States aside From the Division of Psychiatry and Medi- cine, Massachusetts General Hospital, Bos- from disorders involving substance abuse. Generalized anxiety disorder has a lifetime ton. Address reprint requests to Dr. Fric- prevalence of 5 percent. The criteria for diagnosis, as specified by the Diagnostic and Sta- chione at the Division of Psychiatry andtistical Manual of Mental Disorders, fourth edition, are summarized in Table 1.2 The onset Medicine, Massachusetts General Hospital, Warren 6, 55 Fruit St., Boston, MA 02114, is usually before the age of 25 years, and the incidence in men is half that in women. or at gfricchione@partners.org.
Untreated, the typical course is chronic, with a low rate of remission and a moderate re-currence rate.3 N Engl J Med 2004;351:675-82.
Copyright 2004 Massachusetts Medical Society. Risk factors for generalized anxiety disorder include a family history of the condi- tion, an increase in stress, and a history of physical or emotional trauma.4,5 An associa-tion has also been reported between smoking and anxiety, and the risk of generalizedanxiety disorder among adolescents who smoke heavily is five to six times the risk amongnonsmokers.6 Traits such as nervousness and social discomfort may predispose peopleto both nicotine dependence and anxiety.7 Medical illnesses are often associated withanxiety.8 For example, generalized anxiety disorder occurs in 14 percent of patients withdiabetes.9 c o e x i s t i n g p s y c h i a t r i c i l l n e s s e s Major depression is the most common coexisting psychiatric illness in patients withgeneralized anxiety disorder, occurring in almost two thirds of such patients. Panic dis-order occurs in a quarter of patients with generalized anxiety disorder, and alcohol abusein more than a third.1,10 Studies of twins suggest a shared genetic propensity to bothgeneralized anxiety disorder and major depression,11 and a recent report suggests thata genetic variant of the serotonin-transporter gene may predispose people to both con-ditions.12 In prospective studies, anxiety almost always appears to be the primary dis-order and to increase the risk of depression.13 Patients who have generalized anxietydisorder along with coexisting psychiatric illnesses have more impairment, seek moremedical attention, and have a poorer response to treatment than those without coexist-ing illnesses.14 Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine a s s e s s m e n t o f d e p r e s s i o n a n d s u i c i d e r i s k
s t r a t e g i e s a n d e v i d e n c e When generalized anxiety disorder complicates d i a g n o s i s
major depression, there is an increased risk of sui- Patients with generalized anxiety disorder often cide.18 Patients should be asked about depressivehave physical symptoms, and it may be difficult to symptoms, including suicidal ideation. If answersdistinguish the symptoms from those of medical ill- suggest that the patient is at risk for suicide, a psy-nesses that are associated with anxiety.15 Factors chiatric evaluation should be performed as soon assuggesting that anxiety is the symptom of a medical possible.
disorder include an onset of the symptoms after theage of 35 years, no personal or family history of anx- iety, no increase in stress, little or no avoidance of
anxiety-provoking situations, and a poor response pharmacotherapy
to antianxiety medication.16 A physical cause should In part because depression is frequently associated
be suspected when anxiety follows recent changes in with generalized anxiety disorder, antidepressant
medication or accompanies signs and symptoms of agents are often used as first-line agents for treat-
a new disease.
ing the latter condition.19 Commonly used agents In evaluating patients for generalized anxiety and their doses and side effects are summarized in disorder, practitioners should routinely consider Table 2.
medical conditions (e.g., cardiac, pulmonary, neu-rologic, or endocrine illnesses, including hyperthy- Tricyclic Antidepressantsroidism), drug use (e.g., cocaine and other stimu- Tricyclic agents are effective for treating patientslants, such as caffeine), drug withdrawal (e.g., who have generalized anxiety disorder alone or incessation of the use of alcohol, opiates, or benzodi- association with depression.20,21 In one random-azepines), and both prescribed and over-the-coun- ized, controlled trial, the response to imipramineter medications (e.g., corticosteroids, sympathomi- was significantly greater than the response to pla-metics, and herbal medicines, such as ginseng).10,15 cebo, with an improvement in symptoms that was Before making a diagnosis of generalized anxi- more than 50 percent at eight weeks.21 When first ety disorder, practitioners should take a history initiated, tricyclic agents can cause jitteriness andand perform a physical examination in order to insomnia, and thus treatment should be initiatedrule out medical causes of anxiety. Laboratory test- at half the usual dose. Tricyclic therapy can be ham-ing should be guided by the clinical presentation. pered by side effects, which may reduce a patient’sThe cost-effectiveness of specific laboratory test- adherence to treatment (Table 2). ing is uncertain, but given the increased prevalenceof generalized anxiety disorder among patients with Selective Serotonin-Reuptake Inhibitorshyperthyroidism, measurement of thyrotropin is The efficacy of selective serotonin-reuptake inhibi-reasonable.17 tors (SSRIs) is similar to that of tricyclics, and SSRIs Other psychiatric disorders that may be misdiag- have a more favorable side-effect profile. In an eight- nosed as generalized anxiety disorder require con- week, randomized, placebo-controlled trial involv-sideration. Whereas generalized anxiety disorder is ing 326 outpatients, those who received paroxetinedefined as worry that is present most of the time for (20 to 50 mg per day) had a significantly higherat least six months, panic disorder is characterized response rate (defined as much or very much im-by recurrent panic attacks, followed by at least one proved, with a reduction in anxiety and better func-month of persistent anxiety about having more at- tioning) than those who received placebo (72 per-tacks. Obsessive–compulsive disorder is manifested cent vs. 56 percent) and a significantly higher rateas intrusive thoughts and ritualistic actions; post- of remission, which was defined as minimal or notraumatic stress disorder as avoidance, numbing, anxiety and no functional impairment (42 percentand hyperarousal; social phobia as severe anticipa- vs. 26 percent).22 These results have recently beentory anxiety accompanying social situations; and so- replicated.23matization disorder as multiple physical symptoms In a follow-up study, patients who had had a re- in the absence of or out of proportion to underlying sponse to paroxetine in the 8-week trial were ran-disease.
domly assigned to continue to take paroxetine or to Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. Table 1. Diagnostic Criteria for Generalized Anxiety Disorder.*
The patient reports having excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).
The patient has difficulty in controlling worry.
The anxiety and worry are associated with three or more of the following six symptoms (with at least some symptoms present for more days than not for the previous 6 months): restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep).† The focus of the anxiety and worry is not confined to features of other types of psychiatric disorders (e.g., panic disorder, social phobia, obsessive–compulsive disorder, separation anxiety disorder, anorexia nervosa, somatization disorder, or hypochondriasis), and the anxiety and worry do not occur exclusively as part of post-traumatic stress disorder.
The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
The disturbance is not due to the direct physiological effects of a medication, substance abuse, or a general medical con- dition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, a psychotic disorder, or a per-vasive developmental disorder.
* Adapted from the American Psychiatric Association.2 † Only one item is required in children.
take placebo for an additional 24 weeks.24 The rate ized anxiety disorder and depression and is effectiveof relapse during this period was 11 percent for pa- when a patient has both conditions.28 In a report oftients receiving paroxetine, as compared with 41 two double-blind, placebo-controlled trials of ex-percent for those receiving placebo. Among the pa- tended-release venlafaxine, the rates of responsetients who continued to receive paroxetine, the rate among patients with generalized anxiety disorderof remission after six months (73 percent) was high- were 58 percent at eight weeks and 66 percent at sixer than the rate at the end of the eight-week study, a months (vs. 36 percent and 39 percent, respectively,finding suggesting that a longer course of treatment for placebo).29 Almost two thirds of patients whoincreases the likelihood of remission.
had no response to venlafaxine at eight weeks did Restlessness can occur with the initiation of SSRI have a response by six months. Remission rates for therapy, so starting doses should be low. Paroxetine venlafaxine were 32 percent at eight weeks and 43is the SSRI that has been studied most extensively percent at six months (vs. 15 percent and 19 percent,for the treatment of generalized anxiety disorder, respectively, for placebo). Caution is warranted withand it is approved by the Food and Drug Adminis- doses of extended-release venlafaxine that are great-tration (FDA) for this indication, but other members er than 225 mg per day, given the infrequent com-of this class of medications, such as citalopram and plication of sustained systolic hypertension, and inescitalopram, have also been shown to have effica- patients with a history of conduction disturbancecy.25,26 Concern about an increased risk of suicide or ventricular arrhythmias, given the risks of theseamong adults taking SSRIs, in particular, is not complications with an overdose.
supported by a review of placebo-controlled studiesinvolving a total of 48,277 depressed patients and Duration of Therapynine antidepressants. The review showed no sig- Responses to the medications discussed above arenificant difference in suicide rates among the study expected within eight weeks when patients are re-groups.27 However, the initiation of treatment with ceiving a therapeutic dose, although longer cours-any antidepressant in a depressed patient requires es may yield more favorable results, particularly inmonitoring for suicidal ideation and behavior.
those patients who have had partial responses. Al-though objective data on rates of relapse and remis- Serotonin–Norepinephrine–Reuptake Inhibitors sion with longer use of the medications are sparse, Extended-release venlafaxine (Effexor XR), a seroto- patients who have a response should generally benin–norepinephrine–reuptake inhibitor, is also ap- advised to continue taking the antidepressant forproved by the FDA for treatment of both general- six months to a year. When a medication is ineffec- Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Side Effects§
-450 2D6 substrate elevation due to enzyme in- , insomnia, constipation, sexual dysfunction, sweat- oxidase inhibitors, and serotonin 1A agonists are , there are no adequate, well-controlled studies in preg- syndrome of inappropriate antidiuretic hormone, cyto- hibition (paroxetine especially; citalopram and e pram are not significant inhibitors), discontinuati (fatigue, dysphoria, psychomotor changes) ing, anorexia, blood pressure elevation, orthostasis, con- duction defects, ventricular arrhythmias, discontinuation effects (fatigue, dysphoria, psychomotor changes); half usual dose used in moderate hepatic or renal impairment flex tachycardia, anticholinergic effects, weight gain, po- dry mouth, constipation, peripheral edema, rhinitis, pain, diarrhea, vomiting, asthma, pharyngitis eb site of the Anxiety Disorders Association of America at women have failed to demonstrate a risk to the fetus. De- able in either animals or pregnant women. D denotes that Nausea, vomiting, dry mouth, headache, somnolence, in- Nausea, somnolence, dizziness, dry mouth, nervousness, Orthostasis, conduction defects, ventricular arrhythmias, re- Sedation, ataxia, hypotonia, paradoxical agitation, memory Dizziness, headache, drowsiness, light-headedness, fatigue, Somnolence, dizziness, ataxia, fatigue, nystagmus, nausea, Somnolence, nervousness, dizziness, tremor es that studies in animals have shown that the drug has tera- diseases for which safer drugs cannot be used or are ineffective) Titration Up
Starting Dose‡
, and SNRI serotonin–norepinephrine reuptake inhibitor isk during
R
Pregnancy†
reatments for Generalized Anxiety Disorder
Psychopharmacologic T
.adaa.org. SSRI denotes selective serotonin-reuptake inhibitor Medication
The pregnancy-risk category is established by the FDA. B denotes that studies in animals do not indicate a risk to the fetus; nant women, or studies in animals have shown an adverse effect on the fetus, but adequate, well-controlled studies in pregnant spite the findings in animals the possibility of fetal harm appears to be remote, if the drug is used during pregnancy togenic or embryocidal effects, but there have been no adequate well-controlled studies in pregnant women, or no data are avail positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious may make use of the drug acceptable despite its risks.
In perinatal and geriatric patients, approximately half the usual doses are used.
Serotonin syndrome can occur when SSRIs, SNRIs, tricyclic antidepressants, serotonin antagonist–reuptake inhibitors, monoamine Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. tive or intolerable, switching to another agent in the term use and is facilitated by treatment with anxio-same class or another class is reasonable, although lytic antidepressants.20this approach has not been extensively studied.30 Benzodiazepines can often be helpful as short- term treatment when antidepressants are initiated, Nonbenzodiazepine Anxiolytic Agents since benzodiazepines rapidly relieve symptoms Buspirone has been shown in double-blind, ran- (whereas antidepressants typically take weeks todomized, controlled trials to have efficacy in the work) and also help alleviate the restlessness or ner-treatment of generalized anxiety disorder.31 It does vousness sometimes associated with the initiationnot cause sedation, physical dependency, or with- of antidepressant therapy. Benzodiazepines can bedrawal. However, it has no antidepressant effect, tapered over a period of several weeks after the an-so it should not be used alone for anxiety with coex- xiolytic effects of an antidepressant have taken hold.
isting depression. A period of two to four weeks or Nevertheless, in selected patients who have a relapselonger is generally needed for a response.
or cannot tolerate tapering of the dose in order todiscontinue the drug, benzodiazepines may be used long term. A meta-analysis of nine studies of com- Double-blind trials have also shown the efficacy of bined benzodiazepine–antidepressant treatment,
benzodiazepines in treating generalized anxiety dis- including SSRIs and tricyclics, for coexisting anxi-
order, but the side effects are a concern (Table 2), ety and depression revealed that combined treat-
particularly in elderly patients.32,33 In one random- ment was more likely than antidepressant therapy
ized trial comparing paroxetine, imipramine, and a alone to reduce anxiety and depression and that it
benzodiazepine among nondepressed patients with was associated with a lower dropout rate.35
generalized anxiety disorder, the benzodiazepine
was the most effective of the three drugs during the psychotherapy
first two weeks, but at eight weeks it was less effec- The most extensively studied psychotherapy for
tive than either antidepressant.34
anxiety is cognitive behavioral therapy.36 This ther- With long-term benzodiazepine use (which is apy, which teaches patients to substitute positive generally defined as use of a therapeutic dose for thoughts for anxiety-provoking ones, usually in-two months or more), patients may become physi- volves 6 to 12 individual sessions at weekly intervals.
cally dependent on the drug. However, addiction is Patients record their thoughts and feelings in dia-infrequent and occurs mostly in patients at risk for ries, noting situations in which they feel anxious andsubstance abuse. To avoid withdrawal symptoms behaviors that relieve the anxiety. They also role-play(which include seizures, hypersympathetic tone, scenes and rehearse responses to anxiety.
and anxiety), the dose can be reduced gradually In one randomized, controlled study, 32 percent (e.g., a 1.0-mg reduction in the dose of lorazepam of patients in the group that received cognitive be-per week or a 0.5-mg reduction in the dose of al- havioral therapy had clinically significant improve-prazolam per week). Slow tapering is especially im- ment at three months, and 42 percent had clinicallyportant for patients taking high-potency and short- significant improvement at six months, whereasacting benzodiazepines such as lorazepam and none of the patients in the control group had signif-alprazolam. Alprazolam can be associated with a icant improvement at three months.37 In a recentsevere discontinuation syndrome, complicated by study that followed subjects from earlier random-dysphoria and delirium. Switching to equipotent ized trials for 8 to 14 years, the condition of half ofdoses of long-acting clonazepam, with alprazolam the patients who had an initial response to cognitiveavailable on an as-needed basis for one week, can behavioral therapy remained markedly improved,make tapering easier.10 approximately one third still had some improve- There are limited data to guide decisions about ment, and the rest had recurrent anxiety and dis- the duration of benzodiazepine therapy. In one ability.38study, among patients taking only diazepam for An alternative approach to cognitive behavioral anxiety, discontinuation after six months resulted therapy is applied relaxation therapy, in which thein a relapse rate of 63 percent within a year.33 How- patient imagines calming situations to induce mus-ever, in most patients, tapering the dose as a means cular and mental relaxation. One randomized, con-of gradual discontinuation is preferable to long- trolled trial comparing cognitive therapy with ap- Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine plied relaxation therapy showed no significant answer “yes” to the question, “During the past four
difference in improvement rates at one year.39 Sim- weeks, have you been bothered by feeling worried,
ilarly, in a review comparing the outcomes of two tense, or anxious most of the time?” Some practi-
studies of applied relaxation therapy with the out- tioners have supported using this question as a
comes of four studies of cognitive behavioral ther- screening technique.48
apy, the response rates at six months were similar
(52 percent for applied relaxation therapy and 41 perinatal management
percent for cognitive behavioral therapy).40 Psy- During pregnancy and the postpartum period, there
chotherapeutic additions to cognitive behavioral is an increased risk that generalized anxiety disor-
therapy are being tried to improve the response rate, der will develop or worsen. Psychotherapy may ob-
although the efficacy of these combined approach- viate the need for pharmacotherapy, but for severe
es is uncertain.36
anxiety (which may be associated with adverseobstetrical outcomes, including premature birth),medication may be necessary.49 There are no data from prospective controlled r e s i s t a n t g e n e r a l i z e d a n x i e t y d i s o r d e r
studies of antianxiety agents administered during The optimal management of generalized anxiety pregnancy or lactation, and recommendations aredisorder that is resistant to either psychotherapy based on observational data alone. Buspirone mayalone or pharmacotherapy alone is uncertain.41 If be safer than some other medications during preg-the patient’s initial response to medication is inad- nancy. Benzodiazepines should not be used in theequate, the dose should be increased as tolerated first trimester because of the risk of oral clefts. Useand then maintained for at least eight weeks. A pa- of benzodiazepines late in the third trimester maytient’s partial response to a medication may war- cause the floppy infant syndrome or neonatal with-rant a longer trial, given data that suggest further drawal. Sedation may occur in breast-fed infants ofimprovement with longer use. Combining psycho- women taking benzodiazepines.49 If benzodiaz-therapy and pharmacotherapy should also be con- epines are used perinatally, the rule is to use thesidered, although data are lacking on whether the lowest effective dose for the shortest period.
combination results in a better outcome than either Although data are limited, SSRIs do not appear approach alone.42 The possibility of an underlying to be teratogenic. However, there have been reportsmedical condition or a coexisting psychiatric illness of neonatal toxicity, such as early delivery, that wasshould be reconsidered in resistant cases.43 unrelated to the duration of fetal exposure and of Little research has been done on the effects of low Apgar scores, including respiratory distress, in combining medications. For patients who have a infants whose mothers were receiving the drugs inpartial response to one medication, combination the third trimester.49,50 When these medications aretreatment with antidepressants and benzodiaz- used prenatally, decisions about which drug to useepines or buspirone, or augmentation with other may be based on apparent reproductive safety inagents, including anticonvulsants (e.g., gabapen- practice (e.g., fluoxetine or citalopram) or on a lowtin or tiagabine), may be helpful.44,45 ratio of the cord drug concentration to the serumdrug concentration, suggesting minimal fetal expo- p r e v e n t i o n
sure (e.g., sertraline or paroxetine).
In one study, college students who were thought to less, concern has been expressed about the use ofbe at risk for depression were randomly assigned paroxetine near delivery because of reports of tran-to an eight-week cognitive behavioral workshop. At sient neonatal withdrawal symptoms, including res-three years, they had fewer episodes of generalized piratory distress, which in some cases has requiredanxiety than students who had undergone only an intensive treatment.49 Breast-fed infants are alsoinitial assessment.46 More research on prevention exposed to antidepressants, and use of the lowestis warranted.
effective dose possible is advised during both preg-nancy and lactation. A detailed discussion of the s c r e e n i n g
use of anxiolytic medications in pregnancy and lac- Screening for generalized anxiety disorder is not tation is beyond the scope of this review but isroutinely advocated in practice.47 However, approx- available elsewhere.52,53 Ultimately, the risk of aimately 90 percent of patients with the condition medication should be weighed against the poten- Downloaded from www.nejm.org by on December 28, 2008 . Copyright 2004 Massachusetts Medical Society. All rights reserved. tial benefits of relief of serious illness and improved a low dose and then increase it during the next threecaretaking abilities, and decisions should be indi- weeks or so until the target dose is reached (Table 2).
vidualized.
A four-to-five-week course of a benzodiazepine (e.g., clonazepam, given at a dose of 0.25 to 0.5 mgtwice daily) may also be useful in reducing restless- ness related to antidepressant therapy and in rapidly There are currently no formal guidelines from U.S. controlling anxiety. One would taper this dose dur-or European professional societies for the manage- ing the next two to four weeks. Patients who prefer ament of generalized anxiety disorder.
nonpharmacologic approach should be referred forcognitive behavioral therapy and relaxation train-ing. These therapies may also be useful in patients who take medication, although data are limited.
During the initiation of drug therapy, patients In patients who present with anxiety as a symptom, can be seen at intervals of two to four weeks, with themedical causes, such as hyperthyroidism, require frequency decreased to every three to four monthsconsideration, as do common coexisting illnesses during maintenance therapy. If medication is effec-such as major depression, panic disorder, and sub- tive, it should be continued for six months to a yearstance abuse. For generalized anxiety alone or anx- and then tapered off, with monitoring for the re-iety that is associated with depression, a reasonable currence of anxiety or depression, a finding thatfirst-line approach is to administer an SSRI or ex- would require reinitiation of treatment. If a psychia-tended-release venlafaxine on the basis of the dem- trist has not been consulted earlier, referral is ad-onstrated efficacy of these drugs and their generally visable after two failed medication trials or whenfavorable side-effect profiles. To minimize side ef- the patient has complex coexisting illnesses or sui-fects, particularly restlessness, one would start with cidal ideation.
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