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Generalized Anxiety Disorder View online at http://pier.acponline.org/physicians/diseases/d086/d086.html

Module Updated: 2013-04-15 CME Expiration: 2016-04-15

Authors Christopher Gale, MB, ChB, MPH (Hon), FRANZCP Jane Millichamp, PhD

Table of Contents 1. Prevention ...... 2 2. Screening ...... 3 3. Diagnosis ...... 5 4. Consultation ...... 8 5. Hospitalization ...... 9 6. Therapy ...... 10 7. Patient Education ...... 18 8. Follow-up ...... 19 References ...... 20 Glossary...... 24 Tables ...... 26

Quality Ratings: The preponderance of data supporting guidance statements are derived from: level 1 studies, which meet all of the evidence criteria for that study type; level 2 studies, which meet at least one of the evidence criteria for that study type; or level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus. Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html Disclaimer: The information included herein should never be used as a substitute for clinical judgement and does not represent an official position of the American College of Physicians. Because all PIER modules are updated regularly, printed web pages or PDFs may rapidly become obsolete. Therefore, PIER users should compare the module updated date on the offical web site with any printout to ensure that the information is the most current available. CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Purpose: This activity has been developed for internists to facilitate the highest quality professional work in clinical applications, teaching, consultation, or research. Upon completion of the CME activity, participants should be able to demonstrate an increase in the skills and knowledge required to maintain competence, strengthen their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Christopher Gale, MB, ChB, MPH (Hon), FRANZCP, current author of this module, was on speakers bureau for Astra-Zeneca, Janssen, and Lilly; and and consulted for Lilly. Jane Millichamp, PhD, current author of this module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. Richard B. Lynn, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations. PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.

Generalized Anxiety Disorder

Top 1. Prevention Recognize that brief interventions may prevent further anxiety symptoms in children, but no similar data exist for adults. 1.1 Reserve preventive strategies for children at higher risk. Recommendations • Recognize that there are no strategies to prevent GAD in adults. • Consider CBT and parent education to prevent the development of GAD in children who exhibit withdrawn or inhibited behavior or early signs of anxiety, such as separation anxiety or simple phobia. • Consider family-based CBT for children who have a parent with a diagnosed anxiety disorder. Evidence • A 2009 systematic review of prospective studies identified 23 papers, 7 of which reported on anxiety, depression with anxiety, or internalizing disorders (disorders relating to distress and fear). Of the studies on anxiety, two noted an association with abuse or neglect, and one found no relationship (1). • A randomized trial compared a 10-week, school-based CBT program with a parental intervention component to monitoring in children who showed early signs of anxiety disorders as determined by self-report and teacher report. Both groups showed improvements immediately after intervention; however, at the 6-month follow-up, only the intervention group maintained improvement, with reduced rates of existing anxiety disorders and prevention of the onset of new anxiety disorders. Results showed that although the intervention and control groups converged at 12 months, the intervention group showed superior gains at the 2-year follow-up (2; 3). • A randomized trial compared a six-session parent education program with cognitive-behavioral components to no intervention in preschool children who displayed inhibited or withdrawn behaviors, a known risk factor for later anxiety disorders. Children whose parents received the educational intervention showed a significantly greater reduction in anxiety diagnoses at the 12- month follow-up but no significant change in measures of inhibition or withdrawal (4). • A randomized trial evaluated the long-term effectiveness of a universal prevention program using CBT components (the Friends program) in school children. Schools were randomly assigned to either intervention or control and 737 children from grades 6 and 9 were enrolled. At 3-year follow- up, 6th graders who received the CBT prevention program had significantly fewer anxiety and depression symptoms than those in the control condition (5). • A randomized trial evaluated the effects of an 8-week preventive intervention (family-based CBT) on children aged 7 to 12 years whose parents had been diagnosed with an anxiety disorder. At 1- year follow-up, 30% of children in the waitlist control condition had developed an anxiety disorder, compared with 0% of children in the family-based CBT condition (6). Rationale • Cognitive-behavioral interventions in children may be helpful in preventing later development of GAD. Comments • There are no data on the prevention of GAD in patients aged over 14 years. The pediatric trials use any anxiety disorder as the outcome. • Internet-based family CBT programs may be useful for young people and their families who cannot access specialist services.

Generalized Anxiety Disorder

Top 2. Screening Consider using appropriate instruments to screen all adults in primary care settings and in children with risk factors. 2.1 Consider screening adults in primary care settings. Recommendations • Consider screening at-risk adults including those with unexplained symptoms, chronic illnesses, comorbid psychiatric disorders, or family history of anxiety disorders. • Screen adults for GAD in primary care settings by:

Asking one question, e.g., “Are you bothered by nerves?” Asking the two questions which comprise the GAD-2: o Do you feel nervous, anxious, or on edge? o Are you unable to stop or control worrying? Using other instruments such as the GAD-7 or the patient questionnaire PRIME-MD • See table GAD-2 Screening Instrument. • See the GAD-7 Screening Instrument. Evidence • The National Comorbidity Survey Replication estimated that 6.1% of the U.S. population will have GAD during their lifetime, and that 2.9% will have GAD in any 12-month period. (7). • A 2007 study measured the accuracy of brief screening tools compared with a structured psychiatric interview in 965 primary care patients. Overall, 19.5% of patients had an anxiety disorder and 7.6% had GAD. For GAD, a GAD-7 score of ≥7 had sensitivity of 95% and specificity of 70%; a GAD-2 score of ≥2 had sensitivity of 95% and specificity of 64%, and a score of ≥3 had sensitivity of 86% and specificity of 83% (8). • A review of 15 epidemiologic studies of GAD in Europe estimated that the 12-month prevalence is between 0.1% to 2.1%, and the 1-month prevalence is in the range of 0.2% to 1.0%. (9). • One question (“Are you bothered by nerves?”) was used to screen for GAD in 801 primary care patients who then were interviewed using the CIDI. When compared with the CIDI, this question was 100% sensitive and 59% specific (LR, 2.30 [CI, 1.80 to 2.93]) (10). • In four general practices, nonclinical staff screened 6700 patients using the patient questionnaire PRIME-MD. Of these patients, 2928 screened positive and 1216 entered further screening. Of the 1216 patients, 308 had GAD, of which 170 had moderate to severe GAD (HAM-A >14) (11). • A 2008 systematic review of the prevalence of anxiety disorders in persons aged over 65 years included 19 studies that reported the rate of GAD. Two community surveys both estimated that 3.7% of older people had GAD. Among older people receiving psychotropic medications, 7.1% had GAD (12). Rationale • GAD is common in the community and in primary care. • In the primary care setting, screening can be accomplished with as few as one or two questions or a valid screening tool. Comments • A study evaluated the accuracy of a screening instrument involving a short GAD prototype (case description) where individuals were asked to self-identify generalized anxiety. This method was compared with the GAD-7. The GAD prototype was superior to, or at least as good as the GAD-7 scale in that participants were able to self-identify GAD based on a case description (13). • Some patients with GAD make frequent visits to their primary care physician with somatic complaints, such as pain, sleep disturbances, and heart palpitations.

Generalized Anxiety Disorder

• There are no national guidelines addressing primary care screening for anxiety disorders in adults. 2.2 Consider screening children with risk factors. Recommendations • Consider screening for GAD in children with:

A parent with an anxiety disorder A mood disorder such as depression Anxiety symptoms such as social phobia or school refusal A family history of anxiety or mood symptoms • See the sample Child Behavior Checklist for Ages 1½ to 5. • See the sample Child Behavior Checklist for Ages 6 to 18. Evidence • A cross-sectional study of 129 children, 48 of whom were the offspring of normal control subjects, 28 of whom had parents with anxiety disorders, 24 of whom had parents with major depression, and 29 of whom had parents with comorbid anxiety and major depression, showed that diagnosable disorders, including anxiety, were significantly more likely in children in all three ‘high- risk’ groups (14). • Data from a prospective, longitudinal cohort study (n=1037) showed that 117 of 135 adults with GAD had comorbid major depressive disorder, and only 18 had GAD alone. In adulthood, 12% of the cohort had comorbid GAD and major depressive disorder. Among this group, onset of depression occurred first in one-third of patients, anxiety occurred first in another third, and onset of depression and anxiety was concurrent in the final third (15). • A prospective, longitudinal cohort study (n=1037) showed that pure GAD was associated with two risk factors: adverse family environment (low socioeconomic status, maltreatment) and childhood behavioral factors (internalizing problems, conduct problems, more inhibited temperament) (16). • A systematic review of measures of child and adolescent anxiety identified 26 studies published between 1980 and 2000. The pooled effect size was 1.23, which indicates that there is a large difference in these scales between pediatric patients with and without a diagnosis. The estimate of the effect size in five studies (209 participants) for the CBCL was 1.55 (CI, 1.10 to 2.00) (17). • A comparison of CBCL scores from parents of 130 children aged 7 to 14 years found that a maternal cutoff T score of 60 on the somatic subscale ruled out GAD correctly in 63% of children. The somatic complaint scale was most correlated with a correct diagnosis of GAD. The investigators concluded that the CBCL was useful for screening for anxiety but less useful for discriminating among anxiety disorders (18). • A longitudinal community study of 933 mother-child pairs noted that children of mothers with GAD had an increased risk for developing panic disorder, social phobia, and separation anxiety disorder by ages 14 to 17 years (19). Rationale • Children with a parent who has an anxiety disorder have a higher risk for developing an anxiety disorder. • Approximately half of all adult patients with GAD were diagnosed with a psychiatric disorder early in life (i.e., by age 15 years). • GAD often occurs comorbidly with other anxiety disorders and/or psychiatric disorders, such as depression and substance abuse, in adolescents. • Two risk factors that have been identified for pure GAD are an adverse family environment and childhood behavior problems. • The CBCL is a sensitive screening test for children.

Generalized Anxiety Disorder

Top 3. Diagnosis Use clinical assessment to diagnose GAD. 3.1 Use patient history as the primary means of diagnosing GAD. Recommendations • Ask about:

Generalized worry Irritability, fatigue, and sleep disturbance Somatic symptoms of anxiety, such as muscle aches, abdominal pain, and shortness of breath • Screen and diagnose adults with GAD in primary care settings by:

Asking one screening question, e.g., “Are you bothered by nerves?” Asking the two questions which comprise the GAD-2 screening tool: o Do you feel nervous, anxious, or on edge? o Are you unable to stop or control worrying? Using a short structured diagnostic questionnaire such as the CIS-R • Ask about possible comorbid psychiatric conditions such as depression and medical conditions to explain any physical symptoms (e.g., hyperthyroidism, asthma, arrhythmias). • See table DSM-IV Diagnostic Criteria for GAD. • See table GAD-2 Screening Instrument. • See table Selected CIS-R Questions for Anxiety. Evidence • A 2007 study measured the accuracy of brief screening tools compared with a structured psychiatric interview in 965 primary care patients. Overall, 19.5% of patients had an anxiety disorder and 7.6% had GAD. For GAD, a GAD-7 score of ≥7 had sensitivity of 95% and specificity of 70%; a GAD-2 score of ≥2 had sensitivity of 95% and specificity of 64%; and a score ≥3 had sensitivity of 86% and specificity of 83% (8). • One question (“Are you bothered by nerves?”) was used to screen for GAD in 801 primary care patients who then were interviewed using the CIDI. When compared with the CIDI, this question was 100% sensitive and 59% specific (LR, 2.30 [CI, 1.80 to 2.93]) (10). • Australian investigators compared diagnoses generated from the patient-completed CIDI-Auto with clinician diagnoses for 262 patients seen at a tertiary anxiety clinic; 12.6% of patients had a CIDI- Auto diagnosis of GAD. The sensitivity of clinician diagnoses was 0.12, and the specificity was 0.96 (κ = −0.03) (20; 21). • In a study from the UK comparing the CIS-R with the SCAN in 101 patients from general practice, the κ statistic for diagnosing anxiety disorders as a group was 0.56 (CI, 0.29 to 0.83) (21). The estimated prevalence of GAD was 4.8% (n=5) using the CIS-R and 1.0% (n=1) using the SCAN. The CIS-R had 95% sensitivity (22). • A study measured the diagnostic accuracy of the CIDI in a UK primary-care population, compared with a psychiatrist-administered long survey (the SCAN). The prevalence of GAD was 6.7%. The CIDI had sensitivity of 100% with specificity of 94% (23). • A narrative review describes the DSM-IV criteria for GAD (24). Rationale • The inter-test reliability of structured interviews is generally poor; however, short, structured questionnaires, such as the CIS-R, can aid in diagnosis and the assessment of severity. Comments • Patients should be asked about depression, other anxiety disorders, and substance abuse, as these conditions frequently co-occur.

Generalized Anxiety Disorder

• In persons with depression or another type of anxiety disorder, it is also important to ask about generalized worry. • A 2012 meta-analysis of the symptom and financial burden from GAD found that GAD significantly increases the number of days of disability a month to around 13 compared with 5 days for people without anxiety disorders (25). • GAD is characterized by excessive worry about everyday events and problems on most days for at least 6 months to the point that the person experiences distress or has marked difficulty performing day-to-day tasks. Increased motor tension (fatigability, trembling, restlessness, and muscle tension), autonomic hyperactivity (shortness of breath, rapid heart rate, dry mouth, cold hands, and dizziness), or increased vigilance and scanning (feeling keyed up, increased startling, and impaired concentration), but not full-blown panic attacks, may be present. • Differentiating the source of worry is highly problematic, particularly in people with depression (26). A good rule of thumb is to consider GAD as co-occurring if the patient complains of worry as well as depression or another anxiety disorder, and treat for GAD if the treatment of the initial disorder does not resolve their problems. • The definition of GAD is likely to change in the DSM-V. 3.2 Defer laboratory testing in patients unless underlying medical disorders are suspected. Recommendations • Obtain laboratory tests only in patients with GAD in whom a medical disorder is suspected to underlie presenting symptoms, such as:

CBC to exclude anemia Serum glucose to exclude hypoglycemia Thyroid function tests to exclude hyperthyroidism Drug screen if abuse of stimulants or other substances is suspected Evidence • The American Psychiatric Association's 2006 practice guideline on psychiatric evaluation of adults suggested that clinicians obtain tests only to exclude disorders that may be causing symptoms or physical signs found during assessment, or to allay patient concerns (27). Rationale • Laboratory tests should be directed by physical exam findings. It is reasonable to screen for common causes of somatic symptoms that would not be clinically apparent. 3.3 Consider other psychiatric disorders, whether separate or concurrent with GAD, or medical disorders with manifestations that can mimic GAD. Recommendations • Consider the following conditions in patients with GAD:

Other anxiety disorders, such as social phobia, simple phobia, panic, and OCD Depression, including depressive episodes in bipolar disorder Organic disorders, such as anemia, hyperthyroidism, hypothyroidism, and hypoglycemia Substance abuse • See table Differential Diagnosis of GAD. Evidence • A study of 1001 primary care patients evaluated the prevalence of mood disorders. Overall, 3.7% of patients had GAD. Among patients with GAD, 89.2% had additional mental health disorders, most commonly major depressive disorder (84.8%), agoraphobia (33.3%), panic disorder (30.3%), social phobia (30.3%), and specific phobia (30.3%) (28).

Generalized Anxiety Disorder

• In a cohort followed from childhood to age 32 years, 117 of 135 participants with GAD aged between 18 and 32 years also had an episode of depression (15). • In a cohort of U.S. veterans, co-occurring depression and GAD strongly predicted all-cause mortality (HR, 4.29 [CI, 2.92 to 6.36]) (29). Rationale • Manifestations of GAD may overlap with those of other psychiatric and medical conditions. Comments • GAD generally makes treatment of co-occurring disorders more difficult and adversely affects prognosis.

Generalized Anxiety Disorder

Top 4. Consultation Consider consulting a specialist for help in diagnosing patients with suspected GAD. Refer to a service that systematically approaches anxiety disorders. 4.1 Consider consulting a psychiatrist or psychologist for complex cases. Recommendations • If there is diagnostic uncertainty, obtain a second opinion from a psychiatrist, who may consider using a semi-structured interview to clarify the diagnosis or diagnoses. Evidence • Consensus Rationale • Semi-structured interviews administered by an experienced clinician are the gold standard for psychiatric diagnoses. Although this approach has shown good reliability between reviewers, the inter-instrument reliability is poor. Comments • The two types of diagnostic interview are the fully structured interview, which is designed for lay administration, and the semi-structured interview, which requires more clinical judgment. The SCAN and the SCID-IV are semi-structured, and interviewers need to be trained in administering and interpreting them to ensure reliable diagnoses. • The issue of co-occurring disorders needs to be considered as there is little risk for self harm with ‘pure’ GAD but there is considerable risk with commonly co-occurring disorders, such as depression (30). • The SCID-IV and the SCAN can take several hours to administer. • Most experienced clinicians using a standard interview can and will give an expert opinion, but this approach is less reliable than a semi-structured interview. 4.2 Refer patients to mental health experts, particularly when GAD co-occurs with other anxiety disorders. Recommendations • Refer patients with complex or severe GAD to a mental health expert who will use a modular approach which allows flexibility in introducing modules that deal with the symptom clusters that occur in anxiety and depression, such as the Coordinated Anxiety Learning and Management approach. Evidence • A primary trial of psychological interventions used in a planned and modular manner compared with usual care did not make any significant change in the use of medications, but did lead to improvements in response and remission at 6 months. This improvement continued to 18 months (81). Rationale • A systematic and planned method is superior to usual care.

Generalized Anxiety Disorder

Top 5. Hospitalization Hospitalize patients who are actively suicidal. 5.1 Assess suicide risk in all patients with GAD. Recommendations • Assess suicide risk in all patients with GAD and co-occurring disorders, and immediately refer suicidal patients to an appropriate extended-hours mental health service. Evidence • A prospective cohort study followed patients with GAD and major depressive disorder up to the age of 32 years. Many patients with GAD (72%) had depression as well. Among patients with both disorders, 11% attempted suicide (15). Rationale • Suicidal ideation is not uncommon in persons with GAD and GAD with depression. Plans to attempt suicide are less common. Comments • Most people with GAD are treated in outpatient settings; hospitalization of people with GAD is rare. • It is worth considering, however, that GAD co-occurs with other psychiatric disorders and this risk probably relates to the co-occuring condition, particularly depression and PTSD rather than GAD alone (30). • There is no evidence that hospitalization prevents suicide in patients with GAD.

Generalized Anxiety Disorder

Top 6. Therapy Consider the use of non-drug modalities as initial treatment in patients with GAD and offer medication to some patients. 6.1 Use CBT as the cornerstone of treatment in adults and children. Recommendations • If available, initiate CBT in adults with GAD.

Recommend 12 to 20 sessions that include teaching relaxation and anxiety management and challenging cognitive distortions and attributions of bodily functions to pathology. • Recommend a 6- to 10-week individual or group CBT program as initial treatment in children with GAD. For children with GAD, encourage parental involvement in the CBT program (i.e., family- based CBT) to increase treatment gains. Evidence • A 2008 systematic review compared CBT with placebo for adults with anxiety in 25 trials. Overall, patients receiving CBT had less severe anxiety and were more likely to respond to treatment (OR, 4.06 [CI, 2.78 to 5.92]) (31). • A 2012 systematic review of CBT for anxiety in older adults included 12 randomized trials. At 6, but not 3 or 12 months of follow-up, CBT was superior to other treatments but the effect size was small (32). • In a randomized, controlled trial, 45 young people, 21 (47%) of whom had GAD, were assigned to individual CBT, group CBT, or a waitlist control group. Results showed that significantly larger numbers of participants in the two CBT groups were in remission compared with those in the waitlist control group (33). • A randomized, controlled trial comparing individual CBT vs. family CBT vs. family-based education/support/attention (n=161 children aged 7 to 14 years, 88 with GAD) showed individual GAD and family CBT were superior to family education/support/attention (effect size 0.75 and 0.48 respectively). When both parents themselves had an anxiety disorder, family CBT was superior to individual CBT (34). • A randomized, controlled trial of CBT vs. short-term psychodynamic psychotherapy (30 sessions each) in patients with GAD showed superiority of CBT at 6 months (effect size: HAM-A, 0.65; PSWQ, 1.04; and BAI, 0.37) (35). • In a randomized, controlled trial of CBT vs. enhanced usual care in older adults with GAD (n=134), two of three symptom scales showed statistically significant improvement (effect size: PSQW, 0.85 [0.49 to 1.70]; GADSS, 0.27 [0.07 to 0.61]; SIGH-A, 0.13 [−0.21 to 0.47]) (36). • A 2012 randomized, controlled trial in children aged 7 to 13 years compared: standard manual treatment (CBT for anxiety, CBT for depression, and behavioral parent training for conduct problems); modular treatment (an integrated, individualized approach incorporating the three treatments used as specified in the standard condition); and a usual-care condition. The modular treatment is a flexible approach which allows for the primary problem to be addressed as well as co-morbid problems by adding other modules as needed. Community clinicians (n=84) were randomly assigned to deliver one of the three treatment conditions to a total of 174 youths aged 7 to 13 years. The modular treatment resulted in significant improvements in problem areas, with the modular treatment group receiving significantly fewer diagnoses than youths in the usual care or standard treatment groups (37). • A 2005 meta-analysis included 19 studies. Thirteen studies compared CBT with no treatment, (effect size, 0.82 [CI, 0.62 to 1.01]), and 6 studies compared CBT with benzodiazepines (or ‘pharmacotherapy’) (effect size, 0.22 [CI, −0.02 to 0.67]) (38). • A 2007 meta-analysis of 108 controlled trials estimated the effect sizes (all pretreatment to posttreatment) in patients with GAD at 2.06 for CBT, 2.08 for relaxation plus CBT, 1.72 for

Generalized Anxiety Disorder

relaxation and exposure, 2.02 for CBT plus exposure, and 1.54 for CBT plus relaxation and exposure (39). • A 2005 Cochrane review of CBT for anxiety disorders in children included 13 trials. There was a higher response rate in the CBT group (NNT, 3 [CI, 2.5 to 4.5]) (40). Rationale • There is good evidence of the efficacy, long-term benefits, and lack of negative side effects of CBT. Comments • In patients receiving therapist-administered CBT treatment for GAD, spouse/partner hostility independently predicted poor outcome (41). • Parents of children with GAD should be encouraged to participate in CBT in parent group sessions, if available. 6.2 Consider CBT-based self-help therapy. Recommendations • If access to therapist-administered CBT is not available, recommend self-help options based on CBT (e.g., internet-based therapy and bibliotherapy) for treatment of GAD. • For children with GAD, consider parent-administered CBT when access to an approved service provider is limited or delayed. Evidence • A randomized trial of parent-implemented CBT via bibliotherapy (written or computerized materials) compared with waitlist found that bibliotherapy was more effective in reducing children's symptoms of anxiety than waitlist but was less effective than group CBT (42). • A study evaluated the use of parent-implemented, CBT-based bibliotherapy in conjunction with one of three therapist-supported conditions (therapist-initiated telephone sessions, therapist-initiated e-mail sessions, or parent-initiated sessions) in children with anxiety disorders. All three CBT conditions were more effective than waitlist, with the therapist-initiated telephone sessions being the most effective of all (43). • A 2012 systematic review of self-help interventions for adult patients with anxiety disorders found that self-help was significantly more effective than waitlist (effect size, 0.84). Larger effect sizes were reported for guided self-help interventions (0.97) and for web-based/multimedia interventions (0.90), when separated from other self-help modalities (44). Rationale • There is evidence that self-help interventions involving CBT are effective in treating anxiety disorders (including GAD) in adults. • CBT-based bibliotherapy is more effective than waitlist or no treatment in children with anxiety disorders and also is a good stop-gap measure when waiting periods exist for face-to-face CBT or when there are barriers to accessing services. Comments • Studies evaluating self-help CBT have generally included patients with a range of anxiety disorders, rather than GAD specifically. 6.3 Use antidepressants as first-line drug therapy in conjunction with CBT or in patients who need additional therapy. Recommendations • Consider the following antidepressants in treating GAD:

In adults, use escitalopram, paroxetine, sertraline, imipramine, venlafaxine, or duloxetine. In children, use fluvoxamine, venlafaxine, or fluoxetine. • Consider antidepressants rather than CBT in elderly patients.

Generalized Anxiety Disorder

• Be aware that prolonging treatment may reduce relapse. • See table Drug Treatment for GAD. Evidence • A 2005 British guideline for the treatment of anxiety disorders was based on four systematic reviews. The guideline suggested that escitalopram, paroxetine, sertraline, imipramine, and venlafaxine were effective in the short term, that escitalopram, paroxetine, and venlafaxine were effective in the long term, and that paroxetine and escitalopram prevented relapse (45). • SSRIs (escitalopram, paroxetine, sertraline)

A randomized, controlled trial compared sertraline with placebo in participants with moderate to severe GAD over 10 weeks. There was a statistically significant difference in HAM-A scores and response rates (46). A randomized, controlled trial comparing escitalopram, 5 to 20 mg/d, with paroxetine, 20 mg/d, showed a significant difference in HAM-A and CGI scores between paroxetine and escitalopram, 10 mg/d (47). A randomized, controlled trial of 597 outpatients with GAD compared escitalopram, 10 to 20 mg/d, with venlafaxine, 75 to 225 mg/d, and found significant improvement with venlafaxine but not escitalopram on HAM-A scores; however, there was no difference in remission or response rate between treatment and placebo (48). A randomized, controlled trial comparing paroxetine and sertraline showed equivalent reductions in HAM-A scores (49). An open trial with blinded raters compared sertraline, up to 150 mg/d, with 15 sessions of CBT in persons aged over 60 years. In this group, using a completer analysis, 44% of participants who received CBT and 57% of participants who received sertraline were classified as responders. Patients in the sertraline, but not the CBT, group showed significant improvement when compared with those in the waitlist control group (50). A randomized, controlled trial comparing escitalopram, 10 to 20 mg/d, with placebo in 177 older adults with GAD showed improvement in the CGIS (effect size, 0.93 [0.50 to 1.36]) and in PSWQ (effect size, 0.30 [0.23 to 0.48]) (51). A 2007 systematic review of drug treatment of anxiety in children cited three randomized, controlled trials using fluvoxamine, up to 300 mg/d; sertraline, up to 50 mg/d; and fluoxetine, up to 20 mg/d. All three treatments were effective when compared with placebo (52). • SNRIs (duloxetine, venlafaxine)

In a 10-week, double-blind, flexible-dose trial, 327 adult outpatients with GAD were randomly assigned to duloxetine, 60 to 120 mg/d, or placebo. The primary efficacy measure was mean change from baseline to end-point in HAM-A total score. Patients who received duloxetine showed significantly greater improvement in HAM-A total scores (−8.12 vs. −5.89, P=0.02) than patients who received placebo (53). A multicenter, randomized, double-blind, flexible-dose trial that included 487 adult patients with GAD compared duloxetine, 60 to 120 mg/d (n=162); venlafaxine extended release, 75 to 225 mg/d (n=164); and placebo (n=161) over 10 weeks. The primary efficacy outcome measure was mean change from baseline to end-point in the HAM-A total score. Significantly greater improvement in the total score occurred in the duloxetine group (HAM-A change, −11.80; P<0.01) and the venlafaxine extended-release group (HAM-A change, −12.40; P<0.001) compared with the placebo group (HAM-A change, −9.19) (54). A second, double-blind, randomized, controlled trial compared duloxetine, 20 mg or 60 to 120 mg/d, and venlafaxine extended release, 75 to 225 mg/d, with placebo in adult outpatients (n=581) with GAD. All three active treatments significantly improved HAM-A total scores compared with placebo; however, only duloxetine, 60 to 120 mg, and venlafaxine extended-release showed significantly greater improvement than placebo on HAM-A somatic factor scores (55). A reanalysis of two randomized, controlled trials compared venlafaxine extended-release with placebo in children with GAD for an 8-week period. Patients receiving venlafaxine showed statistically significant improvements in the K-SADS anxiety subscale symptom count, HAM-A, SCARED, and the Pediatric Anxiety Rating Scale. A pooled analysis indicated that the children in the venlafaxine group had a significantly greater mean decrease in K-SADS symptom count when compared with those in the placebo group (56).

Generalized Anxiety Disorder

A trial of continuation of treatment among 429 patients who had responded previously (over 26 weeks) to duloxetine, 60 to 120 mg/d, showed 41.8% of patients receiving placebo relapsed over the 26-week continuation phase, compared with 13.7% of patients who continued treatment with duloxetine (57). A study evaluating venlafaxine extended-release vs. placebo as continuation therapy (between 6 and 12 months) in participants who had previously responded to venlafaxine found that continuation of this medication to 12 months significantly reduced relapse rates (58). Rationale • The risk profile of the antidepressants in GAD is similar to that of other options. • In the elderly, sertraline may be superior to CBT. Comments • SSRIs and SNRIs often are associated with transient adverse events, particularly increased anxiety and nausea. These harms can be minimized by starting well below the therapeutic dose range and slowly increasing to an adequate dose. • It can take 6 to 12 weeks of treatment at a therapeutic dose to obtain the full anxiolytic effect from an SSRI or SNRI. Imipramine causes a significant amount of sedation in therapeutic doses, and there is a risk for arrhythmia, particularly in overdose. 6.4 Balance the benefits and harms of benzodiazepines in the treatment of GAD. Recommendations • Consider alprazolam or diazepam in the short-term treatment of GAD. • Balance the risk for dependence and cognitive impairment against symptomatic benefits. • See table Drug Treatment for GAD. Evidence • A 2005 British guideline on the management of anxiety was based on four systematic reviews. The guideline suggested that alprazolam and diazepam were effective in the short term and that diazepam enhances the effect of psychological treatment in patients who are initially unresponsive (45). • A review noted that chlordiazepoxide was superior to placebo and as effective as propranolol over 3 weeks (59). Rationale • Benzodiazepines are effective for anxiety in adults, but have significant side effects. Comments • Benzodiazepines have equivalent efficacy and fewer side effects than pregabalin, azapirones, and herbal therapies in adults. • Many of the original studies on the use of benzodiazepines are dated. Benzodiazepines have been used as controls in other studies and seem to be as effective as many of the newer options. 6.5 Consider azapirones such as buspirone instead of benzodiazepines in the treatment of GAD. Recommendations • Consider buspirone, gepirone, or ipsapirone as alternatives to benzodiazepines in treating GAD. • Be aware that dizziness and drowsiness may occur in patients taking azapirones. • See table Drug Treatment for GAD. Evidence • A 2006 Cochrane review of the azapirones (buspirone, gepirone, and ipsapirone) identified 36 randomized, controlled trials. The pooled mean difference in HAM-A score was 4.3 points (CI, 1.3 to 7.3). The authors identified eight randomized, controlled trials that reported dropout rates,

Generalized Anxiety Disorder

which were significantly lower in the azapirone group. Among three randomized trials using the HAM-A, one found no difference in anxiety between buspirone and placebo (WMD, 0.4 [CI, −5.62 to 6.42]), and two found that buspirone significantly improved outcome compared with placebo (WMD, −7.52 [CI, −9.89 to −5.15] and −3.73 [CI, −4.01 to −3.45], respectively). One randomized, controlled trial (162 participants) reported a response rate based on ‘much or very improved’ scores of 1 or 2 on the CGI. Buspirone significantly improved outcome compared with placebo (RR, 1.48 [CI, 1.01 to 2.17]; P=0.04). The meta-analysis noted a significant increase in dizziness and drowsiness in the treatment group, and there was no difference in mean HAM-A scores between azapirones and benzodiazepines (60). • A 2005 British guideline on the management of anxiety disorders suggested that buspirone, abecarnil, and opipramol were effective in the short term (45). Rationale • Azapirones are effective for GAD, but sedation and dizziness are common side effects. Comments • The newer azapirones (gepirone and ipsapirone) are not available in the U.S. 6.6 Weigh the risks and harms of using atypical antipsychotic medications in GAD. Recommendations • Consider the use of atypical antipsychotic monotherapy as a second-line treatment for GAD. Evidence • Quetiapine

A 2010 Cochrane review identified four trials of quetiapine monotherapy vs. placebo, which led to a superior response rate (n=1396; OR, 2.21 [CI, 1.10 to 4.45]). In the seven placebo-controlled trials of quetiapine monotherapy that used remission as an outcome, quetiapine was superior to placebo (n=2262; OR, 1.83 [CI, 1.01 to 3.12]). However, 36.9% of the participants in the quetiapine group left the study compared with 5.4% of those taking placebo (61). A 2011 systematic review found 17 studies (n=2459), of which 7 were open-label studies without comparators. The trials of adjunctive therapy in individuals with refractory GAD using olanzapine, risperidone, and quetiapine against placebo failed to demonstrate superiority either on symptom remission (five studies, n=874 participants; RR, 1.28 [CI, 0.96 to 1.71]) or on discontinuation for any cause (four studies, n=835; RR, 1.28 [CI, 0.96 to 1.71]). Quetiapine, 150 mg/d, was superior to placebo in achieving remission or response (four studies, n=1346; response RR, 1.31 [CI, 1.20 to 1.44]; remission RR, 1.44 [CI, 1.23 to 1.68]). However, participants taking quetiapine monotherapy were more likely to leave the study than those taking placebo (RR, 1.30 [CI, 1.09 to 1.54]). There was a significant difference in weight gain between quetiapine and placebo (4 lb vs. 1 lb) (62). Another analysis, using the same papers and using a weighted effects model, found a similar result for clinical improvement (or response) (RR, 1 [CI 1.02 to 1.56]) (63). • Olanzapine

A 2010 Cochrane review identified one trial with 24 participants that compared olanzapine, 2.5 to 20 mg, with placebo in addition to antidepressant use. There was no significant difference in response rate or remission rate. There was a mean 0.63 kg greater increase in weight in the quetiapine group over 8 weeks, but in the two studies that examined this, no significant difference was found in the rate of weight gain. There was no significant difference in prolactin level or general extrapyramidal side effects. However, there was an increase in sedation (2 studies, n=858; OR, 2.80 [CI, 1.95 to 4.80]) (61). A 2011 meta-analysis of off-label uses of atypical antipsychotic medications included studies of GAD. Compared with placebo, quetiapine led to higher response rates (RR, 1.26) (63). • Risperidone

Generalized Anxiety Disorder

A 2010 Cochrane review identified one trial with 40 participants that compared risperidone, 0.5 to 2.0 mg, vs. placebo as augmentation of antidepressant use. There was no significant difference in response or remission rate (61). Rationale • Atypical antipsychotics are more effective than placebo but have high rates of side effects. Comments • All studies were 6 to 8 weeks long. • Second-generation antipsychotic medications do not seem efficacious as augmentation of other treatments. • Atypical antipsychotics (as monotherapy) are better than placebo in terms of remission rates but have a greater drop-out rate than placebo. There are significant side effects, and alternate medications are available as monotherapy. 6.7 Consider other medications in treating GAD if antidepressants, azapirones, or benzodiazepines are ineffective or not tolerated. Recommendations • In patients intolerant of first-line medications for GAD, consider:

Pregabalin Propranolol Agomelatine Deramciclane Valproate Ginkgo biloba Kava Hydroxyzine, though sedating side effects are more severe than with other agents • See table Drug Treatment for GAD. Evidence • A 2005 British guideline suggested that hydroxyzine, pregabalin, and the first-generation antipsychotic trifluoperazine each were effective in the short term (45). • A 2010 Cochrane review and meta-analysis of hydroxyzine for GAD included 5 studies. Hydroxizine was more effective than placebo (OR, 0.30 [CI, 0.15 to 0.58]) and tolerable, but had higher rates of drowsiness compared with other agents (OR, 1.74 [CI, 0.86 to 3.53]) (64). • A 2007 systematic review found four good-quality, randomized, controlled trials of pregabalin, 200 to 600 mg/d, compared with lorazepam, alprazolam, or placebo. Pregabalin, 300 to 600 mg/d, in divided doses had equivalent efficacy to benzodiazepines and superior efficacy to placebo over 4 to 6 weeks (65). • A randomized, placebo-controlled trial of pregabalin, 150 to 600 mg/d, in the elderly found a significant reduction in HAM-A scores. There were seven adverse events in the 75 patients receiving pregabalin, three of which were related to the drug (somnolence, increased anxiety, and fracture following a fall) (66). • A 2005 systematic review identified one trial comparing propranolol, 80 to 320 mg/d, with chlordiazepoxide, 30 to 45 mg/d, and placebo over 3 weeks. Both medications were more effective than placebo after 1 week, but no difference was detected between them. Propranolol was found to be more effective than placebo over 3 weeks (59). • A randomized, double-blind, placebo-controlled trial of agomelatine, a melatonin and serotonin agonist, found a significant reduction in HAM-A scores over 12 weeks (67). • A double-blind, randomized, controlled trial comparing deramciclane, a 5-HT2A/2C antagonist (30 mg/d vs. 60 mg/d) and placebo over 8 weeks showed that both doses of deramciclane resulted in clinically significant improvement in HAM-A scores in adult patients with GAD (n=208) (68).

Generalized Anxiety Disorder

• A double-blind, randomized, controlled trial of valproate extended-release (500 mg tid) vs. placebo showed on a completer analysis treatment-related improvement in male patients with GAD (n=74) on HAM-A (69). • A randomized, placebo-controlled trial of ginkgo biloba extract EGb 761 (either 240 or 480 mg/d) in a mixed group (n=107; 82 with GAD, 25 with adjustment disorder with anxious mood) showed significant improvement in HAM-A at both doses (70). • A review of three randomized, double-blind, placebo-controlled trials using two formulations of kava (140 to 280 mg/d) found no benefit in patients with GAD (71). • Tiagabine is not an effective treatment for GAD as reported in three randomized, double-blind, controlled trials that compared it at variable and fixed doses with placebo. All three trials failed to show an improvement in the HAM-A, which was the primary outcome. The authors concluded that there was no evidence for the use of tiagabine for GAD (72). Rationale • Pregabalin and propranolol have proved effective in GAD but have significant side effects. There are data from randomized, controlled trials to suggest that deramciclane, valproate, and ginkgo biloba may also be effective. Comments • Pregabalin is not approved by the FDA for the treatment of GAD and has cognitive side effects. 6.8 Consider other non-drug therapies. Recommendations • In addition to CBT or when CBT is not available, consider:

Relaxation training Worry exposure Acceptance-based therapy Evidence • A 2002 meta-analysis of autogenic training identified 33 randomized, controlled trials. Of these trials, eight studies involved patients with symptoms of anxiety and showed a significant treatment effect; however, none of these studies involved patients with GAD (73). • A 2004 meta-analysis of complementary therapies for patients with anxiety disorders reported an effect size of 0.6 (from 26 trials) for relaxation training in patients with GAD (74). • A randomized, controlled trial of self-exam therapy, which consisted of a 45-page booklet that participants were encouraged to read, showed a significant reduction in anxiety symptoms over a 4-week period (75). • Worry exposure, a component of CBT, was compared with applied relaxation and waitlist control (15 sessions each) in a randomized, controlled trial of 73 outpatients with GAD. Both interventions improved HAM-A, STAI-T, and PSWQ scores; there was no difference between interventions (76). • An open-label, controlled trial of modular psychotherapy (i.e., individual patient-chosen sessions on various anxiety management techniques) did not show any significant difference compared with treatment as usual (77). • A randomized, controlled trial found that short-term psychodynamic psychotherapy is superior to waitlist, but not superior to CBT (35). • Acceptance-based therapy was superior to waitlist control in one randomized, controlled trial (n=31) (effect size: DASS-Anxiety, 0.25; PSWQ, 0.93; clinician rating, 0.30) (78). • Use of exercise as an adjunct therapy to CBT was shown to be somewhat effective in a randomized, controlled trial enrolling outpatients with panic disorder, GAD, or social phobia. An improvement was found in depression scores (effect size, −0.67 [−1.29 to −0.01]) but not anxiety (effect size, −0.16 [−0.77 to 0.45]) (79). Rationale

Generalized Anxiety Disorder

• Data show moderate improvement with relaxation therapy in patients with GAD. • Psychodynamic psychotherapy and acceptance-based therapy in controlled trials are superior to waitlist control. 6.9 Consider combination CBT and drug therapy in children with childhood anxiety. Recommendations • Offer CBT in addition to medication, if available. Evidence • In a group of children (n=488) aged 7 to 17 years with anxiety (mostly co-morbid anxiety conditions), a clinical trial of sertraline alone vs. CBT alone vs. a combination of the two vs. placebo showed that at 12 weeks, 80.7% of the group receiving the combined treatments responded, compared with 54.9% of the sertraline group and 59.7% of the CBT group, and 23.7% of the placebo group (80). Rationale • CBT in combination with medication in children with GAD is superior to either alone.

Generalized Anxiety Disorder

Top 7. Patient Education Recognize the importance of education in treating patients with GAD. 7.1 Monitor response to treatment, and be alert for medication side effects. Recommendations • In adults:

Discuss the long-term nature of GAD. Advise patients of the importance of using non-drug therapies, including CBT, to help manage their anxiety, even if they choose to use medication as well. Advise patients that changing their life circumstances is unlikely to resolve their symptoms. Discuss the risks of medication by class, including suicidal ideation. Mention that patients may develop other symptoms, such as mood disorders or other anxiety symptoms. Advise patients to discuss any new symptoms. • In children:

Advise parents about possible negative side effects of drug therapy. Ask parents to monitor the child for depression/suicidal intent. Discuss a sleep hygiene program and the negative side effects of sleep medication with parents and/or older children. Evidence • Consensus Rationale • There are case reports with antipsychotics of prolonged QTc interval, extrapyramidal side effects, and metabolic syndrome. • Nausea and anxiety are common side effects when starting antidepressants. • Sexual side effects are common with serotonergic antidepressants.

Generalized Anxiety Disorder

Top 8. Follow-up Monitor patients regularly until recovery. 8.1 Monitor patients every 2 to 4 weeks until stable, and follow-up indefinitely thereafter. Recommendations • Consider monitoring patients with a structured instrument, such as the Kessler 6 scale, SIGH-A, or DAS-A. • Review the patient's mental state as well as medication side effects and response to treatment every 2 weeks and then at longer intervals as the patient improves. • See table Kessler 6 Scale. • See table SIGH-A. Evidence • An ongoing follow-up trial to evaluate remission rate found that 25% of adults with GAD will be in full remission after 2 years, and 38% will have a remission after 5 years (82). • An 8-year follow-up study found that 46% of women and 56% of men with GAD who had initially responded to treatment had relapsed (83). • A trial of telephone-based case management in a mixed primary care population showed an improvement in SIGH-A (a self-report version of the HAM-A) scores (84). • The DAS-A has been found to identify significant changes earlier than the HAM-A (85). Rationale • Many patients with GAD have medication side effects and/or increased anxiety as they begin to address cognitive distortions. • The high rate of relapse means that patients with GAD should be monitored indefinitely.

Generalized Anxiety Disorder

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46. Brawman-Mintzer O, Knapp RG, Rynn M, Carter RE, Rickels K. Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2006;67:874-81. (PMID: 16848646) 47. Baldwin DS, Huusom AK, Maehlum E. Escitalopram and paroxetine in the treatment of generalised anxiety disorder: randomised, placebo-controlled, double-blind study. Br J Psychiatry. 2006;189:264-72. (PMID: 16946363) 48. Bose A, Korotzer A, Gommoll C, Li D. Randomized placebo-controlled trial of escitalopram and venlafaxine XR in the treatment of generalized anxiety disorder. Depress Anxiety. 2008;25:854-61. (PMID: 18050245) 49. Ball SG, Kuhn A, Wall D, Shekhar A, Goddard AW. Selective serotonin reuptake inhibitor treatment for generalized anxiety disorder: a double-blind, prospective comparison between paroxetine and sertraline. J Clin Psychiatry. 2005;66:94-9. (PMID: 15669894) 50. Schuurmans J, Comijs H, Emmelkamp PM, Gundy CM, Weijnen I, van den Hout M, et al. A randomized, controlled trial of the effectiveness of cognitive-behavioral therapy and sertraline versus a waitlist control group for anxiety disorders in older adults. Am J Geriatr Psychiatry. 2006;14:255-63. (PMID: 16505130) 51. Lenze EJ, Rollman BL, Shear MK, Dew MA, Pollock BG, Ciliberti C, et al. Escitalopram for older adults with generalized anxiety disorder: a randomized controlled trial. JAMA. 2009;301:295-303. (PMID: 19155456) 52. Reinblatt SP, Riddle MA. The pharmacological management of childhood anxiety disorders: a review. Psychopharmacology (Berl). 2007;191:67-86. (PMID: 17205317) 53. Rynn M, Russell J, Erickson J, Detke MJ, Ball S, Dinkel J, et al. Efficacy and safety of duloxetine in the treatment of generalized anxiety disorder: a flexible-dose, progressive-titration, placebo-controlled trial. Depress Anxiety. 2007;25:182-9. (PMID: 17311303) 54. Hartford J, Kornstein S, Liebowitz M, Pigott T, Russell J, Detke M, et al. Duloxetine as an SNRI treatment for generalized anxiety disorder: results from a placebo and active-controlled trial. Int Clin Psychopharmacol. 2007;22:167-74. (PMID: 17414743) 55. Nicolini H, Bakish D, Duenas H, Spann M, Erickson J, Hallberg C, et al. Improvement of psychic and somatic symptoms in adult patients with generalized anxiety disorder: examination from a duloxetine, venlafaxine extended-release and placebo- controlled trial. Psychol Med. 2009;39:267-76. (PMID: 18485261) 56. Rynn MA, Riddle MA, Yeung PP, Kunz NR. Efficacy and safety of extended-release venlafaxine in the treatment of generalized anxiety disorder in children and adolescents: two placebo-controlled trials. Am J Psychiatry. 2007;164:290-300. (PMID: 17267793) 57. Davidson JR, Wittchen HU, Llorca PM, Erickson J, Detke M, Ball SG, et al. Duloxetine treatment for relapse prevention in adults with generalized anxiety disorder: a double-blind placebo-controlled trial. Eur Neuropsychopharmacol. 2008;18:673-81. (PMID: 18559291) 58. Rickels K, Etemad B, Khalid-Khan S, Lohoff FW, Rynn MA, Gallop RJ. Time to relapse after 6 and 12 months' treatment of generalized anxiety disorder with venlafaxine extended release. Arch Gen Psychiatry. 2010;67:1274-81. (PMID: 21135327) 59. Baldwin DS, Polkinghorn C. Evidence-based pharmacotherapy of Generalized Anxiety Disorder. Int J Neuropsychopharmacol. 2005;8:293-302. (PMID: 15576000) 60. Chessick CA, Allen MH, Thase M, Batista Miralha da Cunha AB, Kapczinski FF, de Lima MS, et al. Azapirones for generalized anxiety disorder. Cochrane Database Syst Rev. 2006;3:CD006115. (PMID: 16856115) 61. Depping AM, Komossa K, Kissling W, Leucht S. Second-generation antipsychotics for anxiety disorders. Cochrane Database Syst Rev. 2010;(12):CD008120. (PMID: 21154392) 62. LaLonde CD, Van Lieshout RJ. Treating generalized anxiety disorder with second generation antipsychotics: a systematic review and meta-analysis. J Clin Psychopharmacol. 2011;31:326-33. (PMID: 21508847) 63. Maher AR, Maglione M, Bagley S, Suttorp M, Hu JH, Ewing B, et al. Efficacy and comparative effectiveness of atypical antipsychotic medications for off-label uses in adults: a systematic review and meta-analysis. JAMA. 2011;306:1359-69. (PMID: 21954480) 64. Guaiana G, Barbui C, Cipriani A. Hydroxyzine for generalised anxiety disorder. Cochrane Database Syst Rev. 2010;(12):CD006815. (PMID: 21154375) 65. Tassone DM, Boyce E, Guyer J, Nuzum D. Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 2007;29:26-48. (PMID: 17379045) 66. Montgomery S, Chatamra K, Pauer L, Whalen E, Baldinetti F. Efficacy and safety of pregabalin in elderly people with generalised anxiety disorder. Br J Psychiatry. 2008;193:389-94. (PMID: 18978320) 67. Stein DJ, Ahokas AA, de Bodinat C. Efficacy of agomelatine in generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol. 2008;28:561-6. (PMID: 18794654)

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68. Naukkarinen H, Raassina R, Penttinen J, Ahokas A, Jokinen R, Koponen H, et al; Deramciclane Dose-Finding Study Group. Deramciclane in the treatment of generalized anxiety disorder: A placebo-controlled, double-blind, dose-finding study. Eur Neuropsychopharmacol. 2005;15:617-23. (PMID: 15949921) 69. Aliyev NA, Aliyev ZN. Valproate (depakine-chrono) in the acute treatment of outpatients with generalized anxiety disorder without psychiatric comorbidity: randomized, double-blind placebo-controlled study. Eur Psychiatry. 2008;23:109-14. (PMID: 17945470) 70. Woelk H, Arnoldt KH, Kieser M, Hoerr R. Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double-blind, placebo-controlled trial. J Psychiatr Res. 2007;41:472-80. (PMID: 16808927) 71. Connor KM, Payne V, Davidson JR. Kava in generalized anxiety disorder: three placebo-controlled trials. Int Clin Psychopharmacol. 2006;21:249-53. (PMID: 16877894) 72. Pollack MH, Tiller J, Xie F, Trivedi MH. Tiagabine in adult patients with generalized anxiety disorder: results from 3 randomized, double-blind, placebo-controlled, parallel-group studies. J Clin Psychopharmacol. 2008;28:308-16. (PMID: 18480688) 73. Stetter F, Kupper S. Autogenic training: a meta-analysis of clinical outcome studies. Appl Psychophysiol Biofeedback. 2002;27:45-98. (PMID: 12001885) 74. Jorm AF, Christensen H, Griffiths KM, Parslow RA, Rodgers B, Blewitt KA. Effectiveness of complementary and self-help treatments for anxiety disorders. Med J Aust. 2004;181(Suppl):S29-46. (PMID: 15462640) 75. Bowman D, Scogin F, Floyd M, Patton E, Gist L. Efficacy of self-examination therapy in the treatment of generalized anxiety disorder. J Counseling Psychol. 1997;44:267-73. 76. Hoyer J, Beesdo K, Gloster AT, Runge J, Höfler M, Becker ES. Worry exposure versus applied relaxation in the treatment of generalized anxiety disorder. Psychother Psychosom. 2009;78:106-15. (PMID: 19218829) 77. Wetherell JL, Ayers CR, Sorrell JT, Thorp SR, Nuevo R, Belding W, et al. Modular psychotherapy for anxiety in older primary care patients. Am J Geriatr Psychiatry. 2009;17:483-92. (PMID: 19461257) 78. Roemer L, Orsillo SM, Salters-Pedneault K. Efficacy of an acceptance-based behavior therapy for generalized anxiety disorder: evaluation in a randomized controlled trial. J Consult Clin Psychol. 2008;76:1083-9. (PMID: 19045976) 79. Merom D, Phongsavan P, Wagner R, Chey T, Marnane C, Steel Z, et al. Promoting walking as an adjunct intervention to group cognitive behavioral therapy for anxiety disorders—a pilot group randomized trial. J Anxiety Disord. 2008;22:959-68. (PMID: 17988832) 80. Walkup JT, Albano AM, Piacentini J, Birmaher B, Compton SN, Sherrill JT, et al. Cognitive behavioral therapy, sertraline, or a combination in childhood anxiety. N Engl J Med. 2008;359:2753-66. (PMID: 18974308) 81. Roy-Byrne P, Craske MG, Sullivan G, Rose RD, Edlund MJ, Lang AJ, et al. Delivery of evidence-based treatment for multiple anxiety disorders in primary care: a randomized controlled trial. JAMA. 2010;303:1921-8. (PMID: 20483968) 82. Yonkers KA, Dyck IR, Warshaw M, Keller MB. Factors predicting the clinical course of generalised anxiety disorder. Br J Psychiatry. 2000;176:544-9. (PMID: 10974960) 83. Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse, and illness—course of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress Anxiety. 2003;17:173-9. (PMID: 12768651) 84. Rollman BL, Belnap BH, Mazumdar S, Houck PR, Zhu F, Gardner W, et al. A randomized trial to improve the quality of treatment for panic and generalized anxiety disorders in primary care. Arch Gen Psychiatry. 2005;62:1332-41. (PMID: 16330721) 85. Morlock RJ, Williams VS, Cappelleri JC, Harness J, Fehnel SE, Endicott J, et al. Development and evaluation of the Daily Assessment of Symptoms - Anxiety (DAS-A) scale to evaluate onset of symptom relief in patients with generalized anxiety disorder. J Psychiatr Res. 2008;42:1024-36. (PMID: 18061206) 86. Singleton N, Bumpstead R, O’Brien M, Lee A, Meltzer H. National Statistics: Psychiatric Morbidity Among Adults Living in Private Households, 2000. London: The Stationery Office; 2000:154. [Full Text] 87. Kessler RC, Andrews G, Colpe LJ, Hiripi E, Mroczek DK, Normand SL, et al. Short screening scales to monitor population prevalences and trends in non-specific psychological distress. Psychol Med. 2002;32:959-76. (PMID: 12214795) 88. Shear MK, Vander Bilt J, Rucci P, Endicott J, Lydiard B, Otto MW, et al. Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A). Depress Anxiety. 2001;13:166-78. (PMID: 11413563)

Generalized Anxiety Disorder

Top Glossary CBC complete blood (cell) count CBT cognitive-behavioral therapy CI confidence interval COPD chronic obstructive pulmonary disease DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th edition FDA Food and Drug Administration GABA γ-aminobutyric acid GAD generalized anxiety disorder HR hazard ratio LR likelihood ratio NNT the number needed to treat OCD obsessive-compulsive disorder OR odds ratio QTc QT corrected for heart rate RR risk ratio SNRI serotonin/norepinephrine reuptake inhibitor SSRI selective serotonin reuptake inhibitor WMD weighted mean difference

Instrument/Scale Acronyms

BAI Beck Anxiety Inventory CBCL Child Behavior Checklist CGI Clinical Global Impression (scale)

Generalized Anxiety Disorder

CIDI Composite International Diagnostic Interview; a fully scripted, lay-administered interview that generates diagnoses CIS-R Clinical Interview Schedule Revision; a scripted, lay-administered interview used in the UK that generates symptom scores DAS-A Daily Assessment of Symptoms - Anxiety Scale; a brief, self-reported scale that identifies early changes in anxiety GAD-2 Generalized Anxiety Disorder 2-item scale GAD-7 Generalized Anxiety Disorder 7-item scale GADSS Generalized Anxiety Disorder Severity Scale HAM-A Hamilton Rating Scale for Anxiety K-SADS Kiddie Schedule for Affective Disorders and Schizophrenia PRIME-MD Primary Care Evaluation of Mental Disorders PSWQ Penn State Worry Questionnaire SCAN Schedules for Clinical Assessment in Neuropsychiatry; a semi-structured interview used in the UK SCARED Screen for Child Anxiety-Related Emotional Disorders SCID-IV Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Axis I Disorders SIGH-A Structured Interview Guide for the Hamilton Anxiety Scale STAI State-Trait Anxiety Inventory

Generalized Anxiety Disorder

Top Tables

Differential Diagnosis of GAD

Disease Characteristics

GAD Chronic excessive anxiety or worry with somatic symptoms such as fatigue, poor sleep, or palpitations Frequently coexists with other mental health disorders. Symptoms are constant and consistent

Acute brain syndromes, including intoxication, withdrawal, and delirium Fluctuating level of consciousness, often with illusions and pseudo-hallucinations, fear, and variations in hyperactivity Variation in presentation over time and disorientation are key findings. Delirium is a medical emergency, and an aggressive search for the cause and appropriate treatment are required

Cardiorespiratory diseases due to asthma, COPD, or coronary heart disease Intermittent wheezing, shortness of breath, and anxiety, which may be due in part to use of β-agonists Chest pain with exertion; may be atypical or may be associated with anxiety Asthma, angina, and COPD can co-occur with GAD, but the generalized nature of the anxiety and symptoms that persist after treatment of pulmonary disorders suggest GAD

Endocrine diseases, including thyroid disorders and diabetes Many endocrine disorders can cause anxiety (most commonly hyperthyroid states and hypoglycemia) or fatigue (not uncommonly hypothyroidism) Generalized worry needs to be assessed after optimization of endocrine disorders

Mood disorders, including major depression, bipolar disorder, depressed mood. and bipolar II disorder Sleep disturbance, fatigue, and anxiety are common in a depressive episode GAD and depressive episodes frequently co-occur. The depressive symptoms should be treated first. As the depression is treated, symptoms of GAD will become more apparent

Other anxiety disorders, including simple and social phobia, panic disorder, OCD, acute stress disorder, Fear and disability (with or without panic symptoms) in one situation occurs in phobias. Panic and posttraumatic stress disorder symptoms (overwhelming fear, palpitations, nausea, weakness, numbness, tremor, and shortness of breath) may occur without any trigger in panic disorder. Recurrent, intrusive, unwanted obsessions and compensatory ritualistic behavior can occur in OCD. Anxiety is a common reaction to trauma or the recollection of trauma. Patients with anxiety disorders frequently have anticipatory anxiety that their symptoms will return GAD can be diagnosed in the presence of any other anxiety disorder if there is disabling, generalized worry in addition to the patient's other symptoms

Substance abuse, e.g., alcohol, benzodiazepines, caffeine, nicotine, amphetamines, cocaine, and other Increased anxiety is a symptom of withdrawal from alcohol and benzodiazepines. People with anxiety stimulants disorders not uncommonly discover that these substances have some effect and begin to abuse them, in part, to control their symptoms. Stimulant (nicotine, caffeine, amphetamines, cocaine, and various ‘party pills') intoxication can cause anxiety If the differential diagnosis is unclear, consider if it is feasible to reassess the patient once he or she is no longer abusing these substances

COPD = chronic obstructive pulmonary disease; GAD = generalized anxiety disorder; OCD = obsessive-compulsive disorder.

Generalized Anxiety Disorder

Drug Treatment for GAD

Drug or Drug Class Dosing Side Effects Precautions Clinical Use

Antidepressants

Selective serotonin reuptake GI side effects, xerostomia, insomnia, Suicidality, particularly in young inhibitors anxiety, agitation, asthenia, platelet adults. Avoid: abrupt discontinuation, dysfunction, drowsiness, headache, other serotonergic drugs, MAOI sexual dysfunction, hyponatremia. therapy. Use low dose with hepatic Rare: serotonin syndrome, NMS disease. Drug interactions due to CYP450 metabolism

Escitalopram (Lexapro) 10-20 mg qd CNS depression Maximum dose 10 mg qd with: hepatic disease, elderly. Caution with CrCl<20

Paroxetine (Paxil) 20-50 mg qd Avoid with pregnancy. Use low dose with: elderly, CrCl<60. Potent inhibitor of CYP2D6

Sertraline (Zoloft) 25-200 mg qd Mild inhibitor of CYPs 2D6, 3A4

Tricyclic antidepressant

Imipramine (Tofranil) Initially, 10 mg qhs. Usual dose: 100- Drowsiness, dizziness, xerostomia, Suicidality in children and young 200 mg total daily dose, dosed qd-qid nausea, constipation, orthostatic adults. Avoid: abrupt withdrawal, MAOI hypotension, tachycardia, cardiac therapy. Decrease dose with hepatic arrhythmias, tremor, weight gain disease. Caution with: GI dysmotility, cardiac disease, seizure history. Obtain ECG at baseline and with dose increases

Serotonin-norepinephrine Nausea, constipation, weight loss, Suicidality, particularly in young reuptake inhibitors xerostomia, insomnia, anxiety, adults. Avoid: abrupt discontinuation, asthenia, dizziness, drowsiness, other serotonergic drugs, MAOI headache, platelet dysfunction, therapy. Caution with: cardiac disease, hypertension, tachycardia, hypertension hyperhidrosis, sexual dysfunction, hyponatremia, serotonin syndrome, rare NMS

Venlafaxine (Effexor, Effexor XR) Extended-release: 75-225 mg qd Decrease dose with: moderate-severe hepatic disease, CrCl<70. Caution with CYP2D6 inhibitors

Duloxetine (Cymbalta) 60-120 mg qd Urinary retention, hepatotoxicity, Avoid with: hepatic disease, severe muscle pain and spasms, CKD, closed-angle glaucoma. Substrate hyperglycemia and moderate inhibitor of CYP2D6

Benzodiazepines CNS depression, respiratory Avoid with: pregnancy, closed-angle Short-term treatment depression, tolerance, dependence, glaucoma. Caution with: CKD, elderly anterograde amnesia, suicidal ideation

Alprazolam (Xanax, Niravam) 0.25-0.5 mg tid. Maximum 4 mg total Constipation, infrequent hematologic Decrease dose with hepatic disease. daily dose, in divided doses toxicity Avoid with potent CYP3A4 inhibitors

Diazepam (Valium) 2-10 mg bid-qid. Maximum 40 mg total Myasthenia Avoid with severe hepatic disease.

Generalized Anxiety Disorder

daily dose Decrease dose with mild-moderate hepatic disease. Substrate of CYPs 2C19, 3A4

Azapirone

Buspirone 15-30 mg total daily dose, dosed bid- Dizziness, drowsiness, nervousness, Avoid with severe hepatic disease. Alternative to benzodiazepines tid headache, nausea Decrease dose with: mild-moderate hepatic disease, CrCl<70. Substrate of CYP3A4

Atypical antipsychotics Drowsiness, dizziness, headache, Mortality in elderly with dementia If antidepressants, benzodiazepines or orthostatic hypotension, increased related psychosis. Avoid: abrupt buspirone are ineffective or not appetite, weight gain, GI side effects, withdrawal, extreme temperatures. tolerated hyperprolactinemia, hyperglycemia, Caution with: pregnancy, diabetes, hyperlipidemia, QT prolongation, EPS, hematologic disease, cardiac or TD, NMS cerebrovascular disease

Olanzapine (Zyprexa, Zyprexa Zydis) 5-10 mg qd Decrease dose with hepatic disease. Caution with CKD. Substrate of CYPs 1A2, 2D6

Quetiapine (Seroquel XR) 50-300 mg qd (extended-release) Hypothyroidism, hepatotoxicity Caution with CKD. Periodic eye exams. Substrate of CYP3A4

Risperidone (Risperdal) 0.5-1.5 mg qd Decrease initial dose with: hepatic disease, CKD. Adjust dose with CYP2D6 inhibitors or inducers

Anticonvulsants CNS side effects (drowsiness, Avoid abrupt discontinuation. Caution If antidepressants, benzodiazepines or dizziness, headache, insomnia, with elderly. Monitor for depression buspirone are ineffective or not asthenia, tremor, others), diplopia, tolerated thrombocytopenia, hypersensitivity reactions, nausea, vomiting, peripheral edema, weight gain

Pregabalin (Lyrica) 300-600 mg total daily dose, dosed Peripheral neuropathy, amnesia, Caution with: HF, pregnancy. Decrease bid-tid angioedema, creatine kinase elevation dose with CrCl<60

Divalproex sodium (Depakote) 500 mg tid Alopecia, elevated blood ammonia, Hepatotoxicity, teratogenicity, menstrual disturbances pancreatitis. Avoid with: hepatic disease, pregnancy. Caution with CKD. Monitor: platelet counts, coagulation. Metabolized by CYPs 2C19, 2C9. Inhibits CYP2C9

Additional agents If antidepressants, benzodiazepines or buspirone are ineffective or not tolerated

Hydroxyzine 50 mg total daily dose, dosed tid Drowsiness, dizziness, anticholinergic Avoid with: glaucoma, MAOI therapy. effects Avoid in first trimester. Caution with: elderly, pulmonary disease, diabetes, seizure disorder, CV disease. Decrease dose with: hepatic disease, CrCl<50.

Propranolol (Inderal) 40-120 mg total daily dose, dosed bid- Bradycardia, hypotension, AV block, Avoid abrupt withdrawal. Avoid tid bronchospasm dizziness, drowsiness, with: advanced AV block, sick sinus

Generalized Anxiety Disorder

diarrhea, nausea syndrome, acute HF. Caution with: CKD, asthma, depression, elderly, hyperthyroidism. Decrease dose with hepatic disease. Substrate of CYP2D6

= first-line agent; = black box warning; AV = atrioventricular; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochromeP450 isoenzyme; ECG = electrocardiogram; EPS = extrapyramidal symptoms; GI = gastrointestinal; HF = heart failure; IM = intramuscular; IV = intravenous; MAOI = monoamine oxidase inhibitor; NMS = neuroleptic malignant syndrome; PO = oral; qd = once daily; qhs = once daily at bedtime; qid = four times daily; SC = subcutaneous; TD = tardive dyskinesia; tid = three times daily PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Generalized Anxiety Disorder

GAD-2 Screening Instrument

During the past month, have you been bothered a lot by:

1. Nerves or feeling anxious or on edge?

0 Not at all

1 Several days

2 More than half of the days

3 Nearly every day

2. Worrying about a lot of different things?

0 Not at all

1 Several days

2 More than half of the days

3 Nearly every day

GAD-2 = Generalized Anxiety Disorder 2-item scale. Reprinted with permission from 8.

Generalized Anxiety Disorder

DSM-IV Diagnostic Criteria for GAD

Excessive anxiety and worry occurring more days than not for 6 months or more

Worry that is difficult to control

At least 3 of the following:

Restlessness or feeling of being ‘keyed up’ or on edge

Easily fatigued

Difficulty concentrating or mind going blank

Irritability

Muscle tension

Sleep disturbance

More than half of the days

Nearly every day

GAD = generalized anxiety disorder. Reprinted with permission from 24.

Generalized Anxiety Disorder

Selected CIS-R Questions for Anxiety

The following questions are concerned with general anxiety/nervousness/tension only:

1. Have you been feeling anxious or nervous in the past month?

2. In the past month, did you ever find that your muscles felt tense or that you could not relax?

IF YES (1 or more days of anxiety or tension)

In the past week, has your anxiety/nervousness/tension been:

Very unpleasant?

A little unpleasant?

Not unpleasant?

3. Have you felt anxious/nervous/tense for more than 3 hours in total on any 1 day of the past week?

4. Which of these symptoms did you have when you felt anxious/nervous/tense?

Heart racing or pounding

Hands sweating or shaking

Feeling dizzy

Difficulty getting your breath

Butterflies in stomach

Dry mouth

Nausea or feeling as though you wanted to vomit

CIS-R = Clinical Interview Schedule Revision; GAD = generalized anxiety disorder. If the patient answers “yes” to either of the first two questions, proceed by asking subsequent questions and apply the following criteria to support the diagnosis of GAD: “Yes” to question 3; OR four or more symptoms in question 4 are present. Adapted from 86.

Generalized Anxiety Disorder

Kessler 6 Scale

In the last 4 weeks, All of the time Most of the time Some of the time Some of the time A little of the time Don't know Refused how often did you feel...

So sad that nothing 4 3 2 1 0 0 0 could cheer you up?

Nervous? 4 3 2 1 0 0 0

Restless or fidgety? 4 3 2 1 0 0 0

Hopeless? 4 3 2 1 0 0 0

That everything was an 4 3 2 1 0 0 0 effort?

Worthless? 4 3 2 1 0 0 0

Reprinted from 87 with permission from Cambridge University Press.

Generalized Anxiety Disorder

SIGH-A

Ask the first question in No symptoms Mild symptoms Preoccupation with Nearly daily symptoms Nearly constant symptoms bold; other questions are symptoms suggested as follow-up questions to elicit further information

What's your mood been like ○ ○ ○ ○ ○ this week? Have you been anxious or nervous? Have you been worrying? Feeling that something bad may happen or feeling irritable?

Have you been feeling ○ ○ ○ ○ ○ tense? Do you startle easily? Cry easily? Are you easily fatigued? Have you been trembling, restless, or unable to relax?

Have you been feeling ○ ○ ○ ○ ○ fearful of situations or events? For example, have you been afraid of the dark, strangers, being left alone, animals, being caught in traffic, crowds, other?

How has your sleeping been ○ ○ ○ ○ ○ this week? Have you had any difficulties sleeping this week? Any problems waking during the night? Waking early and not being able to sleep? Do you feel rested in the morning? Do you have disturbing dreams or nightmares?

Have you had trouble ○ ○ ○ ○ ○ concentrating or remembering things?

Have you been feeling ○ ○ ○ ○ ○ depressed? Have you lost interest in things? Do you get pleasure from friends and hobbies?

Have you been experiencing ○ ○ ○ ○ ○ aches, pains, or stiffness in

Generalized Anxiety Disorder

your muscles? Have you experienced muscle twitching or jerks? Have you been grinding your teeth? Have you had an unsteady voice?

Have you been experiencing ○ ○ ○ ○ ○ ringing in your ears, blurred vision, hot or cold flushes, feelings of weakness, or prickling sensations? (Has this occurred at times other than during a panic attack?)

Have you had episodes of a ○ ○ ○ ○ ○ racing, skipping, or pounding heart? How about pain in your chest or fainting feelings? (Has this occurred at times other than during a panic attack?)

Have you been having ○ ○ ○ ○ ○ trouble with your breathing? For example, pressure or constriction in your chest, choking feelings, sighing, or feeling like you can't catch your breath? (Has this occurred at times other than during a panic attack?)

Have you had any difficulties ○ ○ ○ ○ ○ with stomach pain or discomfort? Nausea or vomiting? Burning or rumbling in your stomach? Heartburn? Loose bowels? Constipation? Sinking feeling in your stomach? (Has this occurred at times other than during a panic attack?)

Have you been experiencing ○ ○ ○ ○ ○ urinary difficulties? For example, have you had to urinate more frequently than usual? Have you had urgency to urinate?

Generalized Anxiety Disorder

Women: Have your menstrual periods been regular? Have you experienced a change in your ability to have an orgasm? Men: Have you had trouble maintaining an erection? Ejaculating prematurely?

Have you been experiencing ○ ○ ○ ○ ○ flushing in your face? Facial pallor? Lightheadedness? Have you been having tension headaches? Have you felt the hair rise on the back of your neck or head as though something had frightened you? (Has this occurred at times other than during a panic attack?)

Patient behavior ○ ○ ○ ○ ○ (Fidgeting, restlessness, or pacing; tremor in hands; furrowed brow; strained face; sighing or rapid respirations; facial pallor; frequent swallowing, etc.)

SIGH-A = Structured Interview Guide for the Hamilton Anxiety Scale. Reprinted from 88.