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CME Objective: To review current evidence for the screening, diagnosis, treatment,and practice improvement of generalized anxiety disorder.
The information contained herein should never be used as a substitute for clinicaljudgment.
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Which patients are at elevatedrisk for generalized anxietydisorder?GAD is twice as common inwomen as in men (6). Patientswith comorbid psychiatric disor-ders (7, 8), obesity (9), history ofsubstance abuse (10), history oftrauma (11, 12), and family historyof GAD (13) are also at increasedrisk for GAD.
A meta-analysis of family and twin studiesof common anxiety disorders showed a sig-nificant association between GAD in pa-tients and their first- degree relatives, with anodds ratio of 6.1 (95% CI, 2.5–14.9) (13).
Are preventive measures usefulfor patients at elevated risk?Although prevention or early in-tervention may reduce the excessdisability due to mental disorders,currently there is no evidence onthe effectiveness of preventivemeasures for GAD in adults.However, in children who exhibitwithdrawn behavior or early signsof anxiety, cognitive behavioraltherapy (CBT) and parent educa-tion can prevent development ofGAD (14, 15), suggesting the pos-sibility of benefit in adults as well.
Should clinicians screen patientsfor generalized anxiety disorder ifthey are at increased risk? If so,how?Although there are no high-qualitystudies demonstrating a benefit toscreening or to early treatment forGAD, the disorder is undertreated:
58% of persons diagnosed withGAD go untreated (16, 17). Asseen in depression care, better detection may be the first step in addressing underdiagnosis and undertreatment and in improvingpatient outcomes (18).
The screening tools to detect GADvary in length and number of addi-tional disorders included in the tool.Two brief and accurate options maybe most feasible in primary care: theGeneralized Anxiety Disorder-2(GAD-2) (see the Box: ScreeningQuestions for Generalized AnxietyDisorder) and the single-itemscreening question, “Are you both-ered by nerves?” In the 2-itemGAD-2 tool, the response to eachquestion is given a score of 0, 1, 2, or3 (for a total score of 0 to 6). A scoreof 3 or more has a sensitivity of 86%and specificity of 83% for detectingGAD in a primary care setting (19).The single item screening question,“Are you bothered by nerves?” has100% sensitivity and 59% specificityamong average-risk primary care pa-tients (20). Alternatively, the Gener-alized Anxiety Disorder-7 (GAD-7)scale (21) and the Primary CareEvaluation of Mental Disorders(PRIME-MD) (22) are slightlylonger screening tools that includeadditional questions to assess symp-tom severity and can thus be used tomonitor symptoms. The 4-item Pa-tient Health Questionnaire (PHQ-4)(23) provides an ultrabrief screen forboth depression and anxiety.
1. Ballenger JC, David-son JR, Lecrubier Y,Nutt DJ, Borkovec TD,Rickels K, et al. Con-sensus statement ongeneralized anxietydisorder from the In-ternational Consen-sus Group on Depres-sion and Anxiety. JClin Psychiatry.2001;62 Suppl 11:53-8. [PMID: 11414552]
2. Kessler RC, Branden-burg N, Lane M, Roy-Byrne P, Stang PD,Stein DJ, et al. Re-thinking the durationrequirement for gen-eralized anxiety disor-der: evidence fromthe National Comor-bidity Survey Replica-tion. Psychol Med.2005;35:1073-82.[PMID: 16045073]
3. American PsychiatricAssociation. Diagnos-tic and StatisticalManual of MentalDisorders, Fifth Edi-tion: DSM-V. 5th ed.Arlington, VA: Ameri-can Psychiatric Pub-lishing; 2013.
Anxiety can be an appropriate response to stressful situations but isconsidered a pathologic disorder when it is disabling and difficult tocontrol. Generalized anxiety disorder (GAD) is the most common
anxiety disorder seen in primary care, affecting approximately 3% of adults inthe United States (1, 2). This disorder is characterized by at least 6 monthsof pervasive and excessive anxiety; recurring worry about common events;and physical symptoms, such as muscle tension, insomnia, and fatigue (3).The disorder is associated with reduced global life satisfaction, decreasedwork productivity, lower health-related quality of life (4), and greater healthcare use and medical costs (4, 5). Primary care physicians can effectivelyevaluate, diagnosis, and manage most patients with GAD.
Kroenke and colleagues found no signifi-cant difference between GAD-7 and GAD-2when screening for GAD in primary carepatients (19).
Patients who screen positive byany tool should be further evaluated
to assess whether they meet diag-nostic criteria according to theDiagnostic and Statistical Manual ofMental Disorders, f ifth edition(DSM-V) (see the Box: Diagnos-tic Criteria for Generalized Anxi-ety Disorder) (3). 4. Revicki DA, Travers K,
Wyrwich KW, Sved-säter H, Locklear J,Mattera MS, et al. Hu-manistic and eco-nomic burden ofgeneralized anxietydisorder in NorthAmerica and Europe.J Affect Disord.2012;140:103-12.[PMID: 22154706]
5. Marciniak MD, LageMJ, Dunayevich E,Russell JM, Bowman L,Landbloom RP, et al.The cost of treatinganxiety: the medicaland demographiccorrelates that impacttotal medical costs.Depress Anxiety.2005;21:178-84.[PMID: 16075454]
6. Gale C, Davidson O.Generalised anxietydisorder. BMJ.2007;334:579-81.[PMID: 17363830]
7. Brawman-Mintzer O,Lydiard RB, Em-manuel N, Payeur R,Johnson M, Roberts J,et al. Psychiatric co-morbidity in patientswith generalized anx-iety disorder. Am JPsychiatry.1993;150:1216-8.[PMID: 8328567]
8. Wittchen HU, Zhao S,Kessler RC, EatonWW. DSM-III-R gener-alized anxiety disor-der in the NationalComorbidity Survey.Arch Gen Psychiatry.1994;51:355-64.[PMID: 8179459]
9. Kasen S, Cohen P,Chen H, Must A. Obe-sity and psy-chopathology inwomen: a threedecade prospectivestudy. Int J Obes(Lond). 2008;32:558-66. [PMID: 17895885]
10. Kessler RC, McGona-gle KA, Zhao S, Nel-son CB, Hughes M,Eshleman S, et al.Lifetime and 12-month prevalenceof DSM-III-R psychi-atric disorders in theUnited States. Re-sults from the Na-tional ComorbiditySurvey. Arch GenPsychiatry.1994;51:8-19.[PMID: 8279933]
11. Brown ES, FultonMK, Wilkeson A, Pet-ty F. The psychiatricsequelae of civiliantrauma. Compr Psy-chiatry. 2000;41:19-23. [PMID: 10646614]
Diagnostic Criteria for Generalized Anxiety DisorderExcessive 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 individual finds it difficult to control the worry.The anxiety and worry are associated with 3 (or more) of the following 6 symptoms (with at least some symptoms
having been present for more days than not for the past 6 months):• Restless or feeling keyed up or on edge.• Being easily fatigued.• Difficulty concentrating or mind going blank.• Irritability.• Muscle tension.• Sleep disturbances (difficulty falling or staying asleep, or restless, unsatisfying sleep).
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 attributable to the physiologic effects of a substance (e.g., drug of abuse, medication) oranother medical condition (e.g., hyperthyroidism).
The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panicattacks in panic disorder, negative evaluation in social anxiety disorder [social phobia], contamination or otherobsessions in obsessive-compulsive disorder, separation from attachment figures in separation anxiety disorder,reminders of traumatic events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physicalproblems in somatic symptoms disorder, body dysmorphic disorder, having a serious illness in illness anxietydisorder, or the content of delusional beliefs in schizophrenia or delusional disorder).
Patients must meet all 6 criteria for a diagnosis of generalized anxiety disorder.
concentrating, irritability, muscletension, or sleep disturbance. Pa-tients must meet all 6 diagnosticcriteria.
What physical examinationfindings indicate possiblegeneralized anxiety disorder?A patient with GAD can appearrestless, irritable, or fatigued. Inprimary care settings, patientswith GAD may also have med-ically unexplained symptoms,such as chest pain and rapid heartrate (18). A thorough physical
What symptoms should promptclinicians to consider a diagnosisof generalized anxiety disorder?GAD is characterized by excessiveand difficult-to-control worriesabout everyday events and prob-lems, resulting in distress ormarked trouble in performing day-to-day tasks. According to theDSM-V (see the Box), the exces-sive anxiety and worry of GAD isassociated with 3 or more of thefollowing symptoms occurring onmore days than not for at least 6 months: restlessness, difficulty
SCREENING... Clinicians might consider screening for GAD among adults who areat increased risk. Multiple screening tools have similar sensitivity and specificity,so a busy clinician might be inclined to use a tool with as few as 1 or 2 questions.
CLINICAL BOTTOM LINE
Diagnosis
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12. Hawker DS, BoultonMJ. Twenty years’ re-search on peer vic-timization and psy-chosocialmaladjustment: ameta-analytic reviewof cross-sectionalstudies. J Child Psy-chol Psychiatry.2000;41:441-55.[PMID: 10836674]
13. Hettema JM, NealeMC, Kendler KS. A re-view and meta-analysis of the ge-netic epidemiologyof anxiety disorders.Am J Psychiatry.2001;158:1568-78.[PMID: 11578982]
14. Dadds MR, HollandDE, Laurens KR,Mullins M, BarrettPM, Spence SH. Earlyintervention andprevention of anxi-ety disorders in chil-dren: results at 2-year follow-up. JConsult Clin Psychol.1999;67:145-50.[PMID: 10028219]
15. Rapee RM, KennedyS, Ingram M, Ed-wards S, Sweeney L.Prevention and earlyintervention of anxi-ety disorders in in-hibited preschoolchildren. J ConsultClin Psychol.2005;73:488-97.[PMID: 15982146]
16. Wang PS, Lane M,Olfson M, Pincus HA,Wells KB, Kessler RC.Twelve-month useof mental healthservices in the Unit-ed States: resultsfrom the NationalComorbidity SurveyReplication. ArchGen Psychiatry.2005;62:629-40.[PMID: 15939840]
17. Kohn R, Saxena S,Levav I, Saraceno B.The treatment gapin mental healthcare. Bulletin of theWorld Health Organ-ization. 2004;82:811-90.
18. Katon W, Roy-ByrneP. Anxiety disorders:efficient screening isthe first step in im-proving outcomes[Editorial]. Ann In-tern Med.2007;146:390-2.[PMID: 17339624]
19. Kroenke K, SpitzerRL, Williams JB, Mon-ahan PO, Löwe B.Anxiety disorders inprimary care: preva-lence, impairment,comorbidity, and de-tection. Ann InternMed. 2007;146:317-25. [PMID: 17339617]
examination is necessary and mayuncover an underlying or co-occurring medical condition thatrequires further evaluation (3).
What laboratory tests shouldclinicians use?No laboratory testing is necessaryto diagnose GAD. However, clini-cians should consider directed labo-ratory testing to exclude medicalconditions suggested by the pre-senting symptoms as well as physicalsigns found during the evaluation(24). Among the most useful tests in patients presenting withsymptoms of anxiety are thyroidfunction tests to exclude thyroiddisease, hemoglobin measurementto exclude anemia, and a urine drugscreen if substance use is a potentialconcern, but other routine labora-tory testing has a low yield. In par-ticular, catecholamine levels tocheck for pheochromocytomashould primarily be limited to per-sons with a family history of en-docrine disorders or those with
What other diagnoses shouldclinicians consider?Several physical and mental disor-ders can mimic or co-occur withGAD (Table 1). In fact, more thanhalf of patients with GAD havecomorbid mental illnesses (6). Inevaluating patients for GAD, clini-cians should consider medical con-ditions (e.g., cardiac, pulmonary, orendocrine illnesses); mood and oth-er anxiety disorders, such as simpleor social phobia, panic disorder, ob-sessive-compulsive disorder, acutestress disorder, and posttraumaticstress disorder; side effects of pre-scribed or over-the-counter med-ications and supplements; andsubstance misuse and withdrawal.Patients with GAD may use alco-hol and benzodiazepines to controlanxiety, so clinicians should be vigi-lant to assess for substance misuse.If symptoms of anxiety persist afterappropriate treatment of physical
Differential Diagnosis for Generalized Anxiety DisorderDisease Notes
Cardiopulmonary disorders (such as asthma, These disorders can co-occur with generalized anxiety chronic obstructive pulmonary disease, disorder or mimic anxiety symptoms. Medications used to or congestive heart failure) treat these disorders, such as β-agonists, may also cause
symptoms mimicking generalized anxiety disorder.Endocrine disease, including thyroid disorders, Many endocrine disorders (most commonly hyperthyroidism,
diabetes, and hypoglycemia hypoglycemia, or hypothyroidism) can mimic anxiety symptoms. Consider thyroid function tests and blood glucose testing. Consider catecholamine level testing, limited to patients with a family history of endocrine neoplasms or those with episodic headaches, hypertension,and palpitations, for evaluation of pheochromocytoma.
Mood disorders, including major depressive Generalized anxiety disorder and mood disorders frequentlydisorder and bipolar disorder co-occur. Symptoms of mood disorders should be treated
first. As the depression is treated, symptoms of generalizedanxiety disorder may become more apparent.
Other anxiety disorders, including simple or Generalized anxiety disorder can be diagnosed in the social phobia, panic disorder, obsessive- presence of any other anxiety disorder if there is disabling,compulsive disorder, acute stress disorder, and generalized worry in addition to other symptoms.posttraumatic stress disorder
Prescribed and over-the-counter medications Corticosteroids, sympathomimetics, and herbal medications(such as ginseng) may mimic symptoms of generalized anxiety disorder.
Misuse of such substances as alcohol, benzo- Stimulant (nicotine, caffeine, amphetamines, cocaine, diazepines, caffeine, nicotine, amphetamine, and various “party pills”) intoxication can cause anxiety cocaine, and other stimulants and mimic generalized anxiety disorder. Anxiety is also a
symptom of alcohol and benzodiazepine withdrawal. Consider ordering a drug screen and taking a detailed history if substance use is suspected.
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20. Means-ChristensenAJ, Sherbourne CD,Roy-Byrne PP, CraskeMG, Stein MB. Usingfive questions toscreen for five com-mon mental disor-ders in primary care:diagnostic accuracyof the Anxiety andDepression Detector.Gen Hosp Psychiatry.2006;28:108-18.[PMID: 16516060]
21. Spitzer RL, KroenkeK, Williams JB, LöweB. A brief measurefor assessing gener-alized anxiety disor-der: the GAD-7. ArchIntern Med.2006;166:1092-7.[PMID: 16717171]
22. Rollman BL, BelnapBH, Mazumdar S,Zhu F, Kroenke K,Schulberg HC, et al.Symptomatic severi-ty of PRIME-MD di-agnosed episodes ofpanic and general-ized anxiety disorderin primary care. JGen Intern Med.2005;20:623-8.[PMID: 16050857]
23. Löwe B, Wahl I, RoseM, Spitzer C, Glaes-mer H, Wingenfeld K,et al. A 4-item meas-ure of depressionand anxiety: valida-tion and standardi-zation of the PatientHealth Question-naire-4 (PHQ-4) inthe general popula-tion. J Affect Disord.2010;122:86-95.[PMID: 19616305]
24. Work Group on Psy-chiatric Evaluation.Psychiatric evalua-tion of adults. Sec-ond edition. Ameri-can PsychiatricAssociation. Am JPsychiatry.2006;163:3-36.[PMID: 16866240]
25. Leichsenring F, Salz-er S, Jaeger U,Kächele H, KreischeR, Leweke F, et al.Short-term psycho-dynamic psy-chotherapy andcognitive-behavioraltherapy in general-ized anxiety disor-der: a randomized,controlled trial. Am JPsychiatry.2009;166:875-81.[PMID: 19570931]
26. Stanley MA, WilsonNL, Novy DM,Rhoades HM, Wa-gener PD, GreisingerAJ, et al. Cognitivebehavior therapy forgeneralized anxietydisorder among old-er adults in primarycare: a randomizedclinical trial. JAMA.2009;301:1460-7.[PMID: 19351943]
and other mental disorders, clini-cians should consider screening forGAD.
Epidemiologic data indicate that 69%–95%of patients with GAD have a co-occurringpsychiatric disorder. Between 45% and 70%of GAD patients had a comorbid mood dis-order, mainly depression, and 38% to 56%had another anxiety disorder, such as panicdisorder, social anxiety disorder, and post-traumatic stress disorder (6).
When should clinicians considerconsulting with a psychologist,psychiatrist, or other specialist?Most patients with GAD can bediagnosed by a primary carephysician. However, in cases of diagnostic uncertainty cliniciansshould consider obtaining a sec-ond opinion from a psychologist,psychiatrist, or other mentalhealth specialist.
them with more rational and realis-tic views (25-29). Clinicians should refer patients to mental health spe-cialists who are specifically trainedin CBT. Other nondrug therapies,described in Table 2, can augmentor replace CBT if it is not availableor is ineffective.
A meta-analysis of 108 controlled trialsassessed the effectiveness of CBT alone,
What nondrug therapies shouldclinicians recommend forgeneralized anxiety disorder?CBT is the cornerstone of treat-ment in adults with GAD (Table 2).The primary goal of this therapy isto help patients identify distressingand dysfunctional beliefs andthought patterns, which are oftenirrational or unrealistic, and replace
DIAGNOSIS... A thorough history is the foundation of diagnosing GAD. Laboratorytesting in patients with GAD can be deferred unless underlying medical disordersare suspected. Comorbid mental illness is common among patients with GAD andshould be assessed in each patient. Clinicians should consider consulting a psychi-atrist, psychologist, or other mental health specialist if the diagnosis of GAD isuncertain.
CLINICAL BOTTOM LINE
Treatment
Nondrug Therapies for Patients With Generalized Anxiety DisorderNondrug Therapy Notes
Cognitive behavior therapy Consists of 12–20 sessions, which can involve education, exposure therapy, relaxation training, and problem-solving techniques.
Short-term psychodynamic psychotherapy Focuses on revealing and resolving unconscious conflicts that are driving anxiety symptoms. Psychodynamic psychotherapy relies on the interpersonal relationship between patient and therapist.
Relaxation training Various techniques that help a patient to relax and reduce anxiety states. For example, progressive relaxation is a technique taught to patients to systematically identify and relax specific muscle groups.
Self-help and self-examination therapy Designed to be conducted predominately independently and consists of therapeutic interventions administered through text or audio/video media to mediate anxiety symptoms.
Worry exposure or exposure therapy The patient stays in an anxiety-provoking or feared situation until the distress or anxiety diminishes. The goal is to learn not react to the situation.
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27. Deacon BJ,Abramowitz JS. Cog-nitive and behavioraltreatments for anxi-ety disorders: a re-view of meta-analyt-ic findings. J ClinPsychol.2004;60:429-41.[PMID: 15022272]
28. Norton PJ, Price EC.A meta-analytic re-view of adult cogni-tive-behavioral treat-ment outcomeacross the anxietydisorders. J NervMent Dis.2007;195:521-31.[PMID: 17568301]
30. Bartley CA, Hay M,Bloch MH. Meta-analysis: aerobic ex-ercise for the treat-ment of anxietydisorders. Prog Neu-ropsychopharmacolBiol Psychiatry.2013;45:34-9.[PMID: 23643675]
31. Baldwin DS, Ander-son IM, Nutt DJ, Ban-delow B, Bond A,Davidson JR, et al;British Associationfor Psychopharma-cology. Evidence-based guidelines forthe pharmacologicaltreatment of anxietydisorders: recom-mendations fromthe British Associa-tion for Psychophar-macology. J Psy-chopharmacol.2005;19:567-96.[PMID: 16272179]
Drug Treatment for Generalized Anxiety DisorderClass of Agent Specific Agent, Daily Dose Benefits Side Effects and Notes
First-line medications: As a class: effective, As a class: nausea, second-generation well tolerated diarrhea, decreasedantidepressants appetite, nervousness,
insomnia, somnolence, impaired sexual function, and hyponatremia
Citalopram, 10–40 mg Few drug interactions See class effectsEscitalopram, 10–20 mg/d Few drug interactions See class effectsParoxetine, 20–60 mg/d Long clinical experience More weight gain and
sexual adverse effects; withdrawal syndrome not uncommon.
Sertraline, 50–200 mg/d Long clinical experience Higher incidence of diarrhea
Duloxetine, 60–120 mg/d Maybe effective in patients Agitation, urine retention; with anxiety and comorbid pain withdrawal symptoms
Venlafaxine, 75–225 mg/d Similar efficacy to other May increase blood second–generation anti- pressuredepressants
Second-line medicationsAzapirones As a class: lack abuse potential As a class: dizziness,
and are not addictive drowsinessBuspirone, 15–30 mg/d Can be used for augmentation See class effectsGepirone, 10–45 mg/d See class benefits Not available in the
United StatesIpsapirone, 10–30 mg/d See class benefits Not available in the
United StatesBenzodiazepines Alprazolam, 0.5–2 mg/d; As a class: very effective, As a class: falls, memory
diazepam, 2–10 mg/d; chlor- particularly in the short term; impairment, riskdiazepoxide, 15–40 mg/d faster onset of action than dependence
antidepressantsThird-line medications Clinicians should consider
consulting with a mental health specialist if unfamiliar with these therapies.
Atypical antipsychotics Olanzapine, 2.5–20 mg/d; Should be reserved for As a class: sedation, risperidone, 0.5 –1.5 mg/d treatment-refractory cases extrapyramidal symptoms,
tardive dyskinesia, weight gain and metabolic side effects.
Antihistamine Hydroxyzine 50–100 mg Potentially useful for treating Sedation, dry mouth, 4 times/d insomnia associated with confusion, and urine
generalized anxiety disorder retentionAnticonvulsant Pregabalin, 300–600 mg/d Well tolerated; effects were Sedation, rash
significant as early as week 1
significant effect on treatment for anxietydisorders (30).
How should clinicians choose anddose drug therapy?For most adults with GAD, clini-cians should offer drug therapy(Table 3) when CBT or other non-drug therapies are not available orare ineffective or if the patient isnot interested in nondrug therapy.Second-generation antidepressants,
CBT plus relaxation, CBT plus exposure,CBT plus relaxation and exposure, and re-laxation and exposure. All tested thera-pies improved pre- to posttreatmentmeasures of anxiety in GAD when com-pared with no treatment. The estimatedeffect size, from greatest to least magni-tude, was 2.08 for relaxation plus CBT,2.06 for CBT alone, 2.02 for CBT plus expo-sure, 1.72 for relaxation and exposure,and 1.54 for CBT plus relaxation and ex-posure (28). A recent meta-analysis failedto show that aerobic exercise had any
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35. Ball SG, Kuhn A, WallD, Shekhar A, God-dard AW. Selectiveserotonin reuptakeinhibitor treatmentfor generalized anxi-ety disorder: a dou-ble-blind, prospec-tive comparisonbetween paroxetineand sertraline. J ClinPsychiatry.2005;66:94-9.[PMID: 15669894]
36. Lenze EJ, RollmanBL, Shear MK, DewMA, Pollock BG,Ciliberti C, et al. Esci-talopram for olderadults with general-ized anxiety disor-der: a randomizedcontrolled trial.JAMA. 2009;301:295-303.[PMID: 19155456]
37. Rynn M, Russell J, Er-ickson J, Detke MJ,Ball S, Dinkel J, et al.Efficacy and safety ofduloxetine in thetreatment of gener-alized anxiety disor-der: a flexible-dose,progressive-titration,placebo-controlledtrial. Depress Anxi-ety. 2008;25:182-9.[PMID: 17311303]
38. Hartford J, KornsteinS, Liebowitz M, Pig-ott T, Russell J, DetkeM, et al. Duloxetineas an SNRI treatmentfor generalized anxi-ety disorder: resultsfrom a placebo andactive-controlled tri-al. Int Clin Psy-chopharmacol.2007;22:167-74.[PMID: 17414743]
40. Schuurmans J,Comijs H, Em-melkamp PM, GundyCM, Weijnen I, vanden Hout M, et al. Arandomized, con-trolled trial of the ef-fectiveness of cogni-tive-behavioraltherapy and sertra-line versus a waitlistcontrol group foranxiety disorders inolder adults. Am JGeriatr Psychiatry.2006;14:255-63.[PMID: 16505130]
41. Fricchione G. Clinicalpractice. Generalizedanxiety disorder. NEngl J Med.2004;351:675-82.[PMID: 15306669]
such as the selective serotonin re-uptake inhibitors, are preferred asfirst-line drug therapy becausethey are as effective as benzodi-azepines but lack the risk for dependency and cognitive impair-ment (31-39). In patients olderthan 60 years, a randomized, con-trolled trial suggested that sertra-line may be superior to CBT fortreating anxiety (40). Patient pref-erence and potential side effectsshould guide decisions on drugtherapy. Short-term treatment withalprazolam or diazepam can rapidlycontrol anxiety symptoms duringthe period before the anxiolyticproperties of an antidepressant takeeffect (41). Clinicians can considerprescribing a benzodiazepine for 4 weeks, followed by a 2- to 4-weektaper. Diazepam may also enhancethe effect of psychological treat-ment in patients who are initiallyunresponsive to this treatmentalone (31). However, cliniciansmust balance the benefits of benzo-diazepines with the risk for de-pendence and cognitive impairmentor delirium.
Azapirones, such as buspirone, arealternatives to benzodiazepines.Two systematic reviews haveshown that azapirones are superiorto placebo and equivalent to ben-zodiazepines in the treatment ofGAD (31, 42). However, sedationand dizziness are common side ef-fects of these drugs and can occurmore frequently than in patientsgiven benzodiazepines. Azapironescan also take weeks to achieve their
effect. If antidepressants, azapirones,or benzodiazepines are ineffectiveor poorly tolerated, alternativemedication options include an-tipsychotics (43, 44), hydroxyzine(31), and pregabalin (31, 45, 46).All have proven effectiveness inGAD but have significant side ef-fects. Clinicians should considerconsulting with a mental healthspecialist before prescribing theseinfrequently used drugs.
How should clinicians monitorpatients?Patients with GAD should be moni-tored in person or by phone every 2 to 4 weeks until stable and thenevery 3 to 4 months during mainte-nance therapy. Structured instru-ments may help clinicians monitorsymptom severity in patients withGAD. However, there is little evi-dence to recommend one instrumentover another and several are available.The PRIME-MD (22) and GAD-7(Table 4) (21) can be used to guidediagnosis and monitor symptoms.Each response in the GAD-7 is as-signed a value of 0, 1, 2, or 3; sum-mary scores of 5, 10, and 15 arecut-off points for mild, moderate,and severe anxiety. There are no for-mal recommendations for treatmentdiscontinuation or augmentationbased on GAD-7 scores. Download-able forms of this instrument areavailable in over 50 languages(www.phqscreeners.com/) (47). Thenew DSM-V includes a variety ofadditional monitoring instru-ments, including one that monitorssymptom severity in adults with
Generalized Anxiety Disorder 7-Item ScaleOver the last 2 weeks, how often have you been bothered by the following problems? Not at all Several days Over half the days Nearly every day
1. Feeling nervous, anxious, or on edge 0 1 2 32. Not being able to stop or control worrying 0 1 2 33. Worrying too much about different things 0 1 2 34. Trouble relaxing 0 1 2 35. Being so restless that it’s hard to sit still 0 1 2 36. Becoming easily annoyed or irritable 0 1 2 37. Feeling afraid as if something awful might 0 1 2 3
happen
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42. Chessick CA, AllenMH, Thase M, BatistaMiralha da CunhaAB, Kapczinski FF, deLima MS, et al. Aza-pirones for general-ized anxiety disorder.Cochrane DatabaseSyst Rev.2006:CD006115.[PMID: 16856115]
43. Ipser JC, Carey P,Dhansay Y, Fakier N,Seedat S, Stein DJ.Pharmacotherapyaugmentationstrategies in treat-ment-resistant anxi-ety disorders.Cochrane DatabaseSyst Rev.2006:CD005473.[PMID: 17054260]
45. Tassone DM, BoyceE, Guyer J, Nuzum D.Pregabalin: a novelgamma-aminobu-tyric acid analoguein the treatment ofneuropathic pain,partial-onsetseizures, and anxietydisorders. Clin Ther.2007;29:26-48.[PMID: 17379045]
46. Montgomery S,Chatamra K, Pauer L,Whalen E, BaldinettiF. Efficacy and safetyof pregabalin in eld-erly people withgeneralised anxietydisorder. Br J Psychi-atry. 2008;193:389-94. [PMID: 18978320]
47. Pfizer. PatientHealth Question-naire Screeners. Ac-cessed at www.phqscreeners.comon 18 June 2013.
48. American PsychiatricAssociation. SeverityMeasures for Gener-alized Anxiety Disor-der. Accessed atwww.psychiatry.org/practice/dsm/dsm5/online-assessment-measures#Disorderon 16 August 2013.
49. Canadian PsychiatricAssociation. Clinicalpractice guidelines.Management ofanxiety disorders.Can J Psychiatry.2006;51:9S-91S.[PMID: 16933543]
GAD (www.psychiatry.org/practice/dsm/dsm5/online-assessment-measures#Disorder) (48). However,these additional instruments havenot been evaluated as rigorously asthe GAD-7 and may be morecumbersome to use in a busy pri-mary care practice. Along withsymptom assessment, cliniciansshould consistently ask about med-ication adherence, treatment sideeffects, and suicide risk.
Pharmacotherapy should be con-tinued for 6–12 months aftersymptom response is achieved (48).After discontinuation of medica-tions, 20%–40% of patients relapsewithin 6–12 months (49, 50). Somepatients with severe chronic anxietyfor many years may require long-term medication (>1 year) (49).
A trial of continuation of treatmentamong 429 GAD patients who had re-sponded previously to duloxetine foundthat only 13.7% of patients who continuedtreatment relapsed over the 26-week con-tinuation phase compared with 41.8% ofpatients receiving placebo during thesame period (50).
When should patients behospitalized?Although most patients with GADcan be treated as outpatients, pa-tients with GAD who are activelysuicidal should be hospitalized.Suicidal ideation is not uncommonin patients with GAD with orwithout co-occurring depression.Clinicians should assess risk forsuicide in all patients with GAD ateach follow-up encounter (51). Manyof the screening and monitoringinstruments do not include a question
about suicidality, so cliniciansmight consider using the followingitem from PRIME-MD: “Over thelast 2 weeks, how often have youbeen bothered by thoughts that youwould be better off dead or of hurt-ing yourself in some way?” (www.phqscreeners.com/).
A meta-analysis of suicide risk among par-ticipants in recent clinical trials of new an-tianxiety medications found that among4333 patients in GAD treatment trial, thecrude death rate due to suicide was 0.05%.Information on suicide attempts was notavailable (51).
Hospitalization might also be re-quired for intractable symptoms,for grave disability, or to addressco-occurring illness. GAD can com-plicate treatment of co-occurring dis-orders and adversely affects prognosis.
In a cohort of U.S. veterans, co-occurringdepression and GAD was associated withincreased cardiovascular mortality (haz-ard ratio, 2.68 [CI, 1.22–5.88]) (52).
When should clinicians considerconsulting a psychologist,psychiatrist, or other specialist?Consultation with a psychologist,psychiatrist, or other specialistshould be considered if patientshave not improved after 12–16weeks of CBT or if they do not re-spond after 6 weeks of first- or second-line medication therapy.Consultation is also warranted ifpatients are unable to tolerate drugtherapy; express suicidal thoughts;or have comorbid substance, mood,or anxiety disorders or if the clini-cian is considering prescribingthird-line medications.
TREATMENT... Primary care physicians play an important role in managing anxi-ety disorders. CBT is the treatment of choice for GAD in most adults. If CBT is notavailable, is ineffective, or if the patient is not interested in nondrug therapy,then second-generation antidepressants are the first-line medication options. Cli-nicians should assess risk for suicide in all GAD patients and refer more complexGAD patients to mental health specialists.
CLINICAL BOTTOM LINE
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50. Davidson JR,Wittchen HU, LlorcaPM, Erickson J, DetkeM, Ball SG, et al. Du-loxetine treatmentfor relapse preven-tion in adults withgeneralized anxietydisorder: a double-blind placebo-con-trolled trial. Eur Neu-ropsychopharmacol.2008;18:673-81.[PMID: 18559291]
51. Khan A, LeventhalRM, Khan S, BrownWA. Suicide risk inpatients with anxietydisorders: a meta-analysis of the FDAdatabase. J AffectDisord. 2002;68:183-90. [PMID: 12063146]
52. Phillips AC, Batty GD,Gale CR, Deary IJ,Osborn D, MacIntyreK, et al. Generalizedanxiety disorder, ma-jor depressive disor-der, and their co-morbidity aspredictors of all-cause and cardiovas-cular mortality: theVietnam experiencestudy. PsychosomMed. 2009;71:395-403.[PMID: 19321850]
53. Stein MB, Sher-bourne CD, CraskeMG, Means-Chris-tensen A, BystritskyA, Katon W, et al.Quality of care forprimary care pa-tients with anxietydisorders. Am J Psy-chiatry.2004;161:2230-7.[PMID: 15569894]
54. National Collaborat-ing Centre for Men-tal Health. NICE Clin-ical Guideline 113:Generalised AnxietyDisorder and PanicDisorder (With orWithout Agorapho-bia) in Adults. Lon-don: National Insti-tute for Health andCare Excellence;2011. Accessed athttp://guidance.nice.org.uk/CG113 on 14June 2013.
Are there measures thatstakeholders use to evaluate thequality of care for patients withgeneralized anxiety disorder?Currently, there are no recommendedmeasures to evaluate the quality ofGAD care. However a study fromthe University of California, SanDiego, used the following 3 metricsas quality indicators in the treatmentof primary care patients with anxietydisorders in university-affiliated out-patient clinics: mental health referral,anxiety counseling, and use of appro-priate antianxiety medications duringthe previous 3 months. In this popu-lation, less than 1 in 3 patients hadreceived anxiety treatment that met asingle quality-of-care indicator (53).These metrics could be implementedfor quality improvement programs;however, their impact on patient out-comes are not yet known.
What do professionalorganizations recommendregarding the care of patientswith generalized anxiety disorder?There are currently no formal prac-tice guidelines from U.S. profession-al societies for the management ofGAD. The United Kingdom’s Na-tional Institute for Health and Clin-ical Excellence (NICE) publishedclinical guidelines for GAD andpanic disorder in 2011 (www.nice.org.uk/cg113). These guidelines de-scribe a stepped-care model forGAD management (54). Step 1 in-volves patient education and activemonitoring as first-line treatment.Step 2 involves low-intensity psy-chological interventions for patientswho do not improve with step 1.Step 3 involves CBT or drug treat-ment for patients who do not re-spond to step 2 or who have markedfunctional impairment. The finalstep, step 4, involves mental healthspecialists, complex drug and/orpsychological treatment regimens,and hospitalization for treatment-refractory patients or individuals atrisk for self-harm or self-neglect.
PracticeImprovement
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Inthe
C linicTool Kit
In the Clinic
GeneralizedAnxietyDisorder
ACP Smart Medicine Modulehttp://smartmedicine.acponline.org/content.aspx?gbosld=58ACP Smart Medicine on generalized anxiety disorder from
http://nihseniorhealth.gov/videolist.html#anxietydisordershttp://nihseniorhealth.gov/anxietydisorders/quizzes.htmlInformation on anxiety from the NIH Senior Health,
including videos and tutorials.www.nimh.nih.gov/health/publications/generalized-anxiety
Cochrane review on psychological therapies for people withgeneralized anxiety disorder, published in 2010, and onsecond-generation antipsychotic drugs for anxietydisorders, published in 2011.
Diagnostic Tests and Criteriahttp://smartmedicine.acponline.org/content.aspx?gbosld=58Screening tools (GAD-2 Screening Instrument; Selected
CIS-R Questions for Anxiety; Kessler 6 Scale; SIGH-AScale) for assessing generalized anxiety disorder fromACP Smart Medicine.
http://smartmedicine.acponline.org/content.aspx?gbosld=58List of laboratory and other tests for generalized anxiety
Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/
to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.
1. A 38-year-old woman is evaluated for a2-year history of irritability and frequentheadaches, accompanied by nausea andsweating. She is a housecleaner and hashad increasing difficulty concentrating atwork over the past year, and it takes hermuch longer to clean houses lately. Shehas a difficult time getting to sleep andfrequently arises after 2 to 3 hours offitful sleep in bed. Her mood is good. Sheworries frequently about her ability topay her bills and what she will do forretirement. She has cut back on activitieswith friends and does not like to go outin social situations anymore. She hasasthma, and her only current medicationis albuterol as needed.
On physical examination, she is afebrile,blood pressure is 130/72 mm Hg, pulserate is 98/min, and respiration rate is14/min. BMI is 22. Serum thyroid-stimulating hormone level, completeblood count, and urinalysis are normal.
Which of the following is the most likelydiagnosis?
A. Attention deficit–hyperactivitydisorder
B. Bipolar disorderC. Generalized anxiety disorderD. Major depressive disorder
2. A 60-year-old woman is evaluated forincreased irritability and anxiety. She wasin an automobile accident 3 months agoin which she was rear-ended by a car ata stop light. Since that time she hasnightmares about the incident and statesshe has not returned to driving for fearof being in another accident. Her sleep ispoor, and her husband states she isbecoming more socially isolated since shehas stopped driving. She has continuedto perform her usual hobbies at home.She has no suicidal thoughts. On physicalexamination, all vital signs are normal.
Which of the following is the most likelydiagnosis?
A. Generalized anxiety disorderB. Major depressive disorderC. Obsessive-compulsive disorderD. Posttraumatic stress disorder
3. An 81-year-old man is evaluated for a 3-week history of shortness of breath,chest pain, palpitations, difficultysleeping, early morning awakening, andlack of interest in getting out of bed inthe morning. The patient’s wife died ofcancer 9 months ago. He says that hehas been seeing her face at night whenhe closes his eyes and frequently awakesat night thinking that she is next to himin bed. Medical history is significant forhypertension and hyperlipidemia.Medications are hydrochlorothiazide,atorvastatin, and diphenhydramine atbedtime as needed for sleep. Results ofthe physical examination are normal.
Chemistry panel and complete bloodcount are normal. Electrocardiogramreveals normal sinus rhythm with leftventricular hypertrophy without ischemicchanges. Chest radiograph is normal.Exercise treadmill test is negative forcardiac ischemia.
Which of the following is the most likelydiagnosis?
A. Anticholinergic drug side effectB. Complicated griefC. Generalized anxiety disorderD. Major depression with psychotic
features
4. A 62-year-old man is evaluated in theemergency department for recent onsetof fever and severe abdominal pain. Healso reports a history of anxiety, frequentpalpitations, difficulty concentrating,dyspnea, diarrhea, nausea, vomiting, andweight loss (total, 9.1 kg [20 lb]) over the
past few months. He has had no neckdiscomfort. An abdominal CT scan withiodine contrast obtained several weeksago when he first experienced abdominalpain was normal. The patient also has a6-month history of Graves diseasetreated with methimazole. He takes noother medication.
Physical examination shows an anxiousand agitated man. Temperature is 38.9 °C(102.0 °F), blood pressure is 160/90 mmHg, pulse rate is 130/min and regular,and respiration rate is 22/min. Cardiacexamination shows a grade 2/6holosystolic murmur, and crackles areheard on lung examination. Eyeexamination shows no acuteinflammatory findings. Findings from anexamination of the pharynx are normal.The thyroid gland is firm and enlargedbilaterally with no specific nodulespalpated. A thyroid bruit is heard. Nocervical lymphadenopathy is noted. Theskin is warm and moist. Abdominalexamination reveals a palpable liver 2 cmbelow the right costal margin.Examination of the extremities shows 2+peripheral leg edema. Neurologicexamination reveals that the patient isoriented to place but not time, giving anincorrect answer when asked for theyear.
Results of laboratory serum studies showa thyroid-stimulating hormone level ofless than 0.01 µU/mL (0.01 mU/L), a freethyroxine (T4) level of 8.2 ng/dL (106pmol/L), and a triiodothyronine (T3) levelof 650 ng/dL (10 nmol/L).
Which of the following is the most likelydiagnosis?
A. Euthyroid sick syndromeB. Myxedema comaC. Subacute thyroiditisD. Thyroid storm
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