Jack M. Gorman Treating Generalized Anxiety Disorder Jack M. Gorman, M.D. Generalized anxiety disorder (GAD) is characterized by chronically persistent worry and therefore requires effective long-term treatment. This article reviews the benefits and risks associated with various pharmacologic and psychological therapies to assess their ability to achieve the elimination of GAD symptomatology and restoration of normal function. Psychotherapeutic approaches such as applied relaxation, cognitive therapy, and cognitive-behavioral therapy have all been shown to be effective when used as monotherapies and may be beneficial when used adjunctively. Current effec- tive pharmacotherapies for patients with GAD include anxiolytic benzodiazepines, buspirone, and an- tidepressants including venlafaxine and paroxetine. Benzodiazepines have long been used to treat anxiety and are particularly appropriate in short-term treatment situations; however, their adverse side-effect profile and their inability to treat depression commonly comorbid with GAD renders them less than ideal in many situations. Buspirone has demonstrated anxiolytic benefits but, like ben- zodiazepines, shows negligible antidepressant action. Antidepressants like paroxetine and venlafaxine are not only effective antidepressants but also effective anxiolytics, thus implying their special ability to treat GAD and concurrent depression, even over the long-term. (J Clin Psychiatry 2003;64[suppl 2]:24–29) eneralized anxiety disorder (GAD) did not become of normal functioning. Although treatment may be com- Gformally diagnosable until 1980 with the publica- plicated by the presence of other psychiatric disorders, tion of the DSM-III. Current DSM-IV diagnostic criteria achieving these treatment goals may decrease the rate include excessive anxiety and worry occurring more days of overutilization of medical services and the occurrence than not for at least 6 months, or trouble controlling exces- of other disorders, but research has yet to confirm this sive worry and anxiety, among others. Despite using dif- hypothesis. This article will review treatment options cur- ferent diagnostic criteria, 2 major epidemiologic surveys rently available to physicians treating GAD and preview found comparable 1-year and lifetime prevalence rates potential future treatments. Current options include vari- in the United States. Data from the Epidemiologic Catch- ous kinds of psychotherapy and a battery of pharmaco- ment Area (ECA) using DSM-III diagnostic criteria therapy classes such as benzodiazepines, azapirones, and showed 1-year prevalence rates of 2.0% to 3.5% and life- antidepressants, among others. This article will also ex- time prevalence rates of 4.1% to 6.6%. Data from the amine how the use of diagnosis and treatment guidelines National Comorbidity Survey (NCS) using DSM-III-R such as algorithms may facilitate implementation of treat- criteria observed similar prevalence rates: 3.1% 1-year ment and the goal of eliminating symptoms and restoring prevalence and 5.1% lifetime prevalence (Figure 1).1 functionality. Despite indications of substantial prevalence, GAD often goes undiagnosed.2 Patients diagnosed with the disorder PSYCHOTHERAPY tend to exhibit chronic functional impairment, seek gen- eral medical services at an elevated rate, and develop Patients with GAD tend to have cognitive abnor- comorbid psychiatric disorders.1 malities that hinder their ability to effectively deal with Effective treatment should ultimately aim at the elimi- symptoms associated with GAD and other aspects of their nation of anxiety symptoms and the complete restoration environment. For example, in patients with GAD, worry impedes the normal processing of information when atten- tion, memory, or problem solving faculties are employed.3 As a result, patients with GAD are more likely to incor- From the Department of Psychiatry, Mt. Sinai School of rectly interpret external stimuli as dangerous or threaten- Medicine, New York, NY. ing,4 regard unlikely events as likely,5 or manifest these This article is derived from the teleconference “Treating symptoms somatically through inordinate muscle tension. Depression and Anxiety to Remission: Use of Algorithms,” which was held April 17, 2002, and supported by an Psychotherapy is designed to help patients develop cog- unrestricted educational grant from Wyeth Pharmaceuticals. nitive or behavioral strategies to effectively manage both Corresponding author: Jack M. Gorman, M.D., Department of Psychiatry, Mt. Sinai Medical School, One Gustave L. Levy cognitive and somatic symptoms that impede normal Place, Box 1230, New York, NY 10029. functionality. 24 © COPYRIGHT 2003 PHYSICIANS POSTGRADUATE PRESS, INC. © COPYRIGHT 2003 PHYSICIANSJ Clin PsychiatryPOSTGRADUATE 2003;64 PRESS (suppl, INC 2). Treatment of GAD Figure 1. 1-Year and Lifetime Prevalence Rates of GAD in the γ-aminobutyric acid (GABA) system at the GABAA the Epidemiologic Catchment Survey and National receptor complex, which leads to reduced neural transmis- Comorbidity Surveya sion throughout the central nervous system.10 Benzodiaze- pines can be short-acting or long-acting, and both kinds Epidemiologic Catchment National Comorbidity Survey Survey have been shown to have a rapid onset of anxiolytic action 7 7 in patients with GAD.11,12 However, their role in long-term Los Angeles, CA St. Louis, MO treatment of anxiety disorders is limited, given evidence 6 6 Durham, NC that more than one third of those treated with benzodiaze- 13 5 5 pines will not remit and, some, but by no means all, stud- ies have found that their effect does not differ significantly 4 4 from placebo after the initial 4 to 6 weeks of treatment.7,14 Failure of benzodiazepines to produce remission in 3 3 a substantial number of patients renders their use difficult Prevalence (%) Prevalence Prevalence (%) Prevalence 2 2 to recommend especially given modern commitments to the higher treatment standard of symptom elimination. In 1 1 addition, benzodiazepines do not effectively ameliorate the principal cognitive symptom of GAD, namely worry, 0 0 1-Year Lifetime 1-Year Lifetime despite being able to positively impact the somatic mani- Prevalence Prevalence Prevalence Prevalence festations of anxiety.11,15,16 Also, benzodiazepines fail to aAdapted with permission from Wittchen et al.1 reduce depressive symptoms and in some cases even exac- erbate them,17 an especially pressing limitation given the high rate at which GAD and depression occur comorbidly. Early psychosocial therapies targeted the somatic Benzodiazepines have also been associated with ad- manifestations of anxiety, such as increased physical ten- verse cognitive side effects such as sedation, hypnotic ef- sion, through relaxation techniques.6 However, Borkovec fects, and motor impairment.12 Abuse among those treated and Whisman7 concluded that cognitive-behavioral ther- with benzodiazepines is uncommon10 and patients treated apy (CBT) produced clinically and statistically significant with benzodiazepines over an extended period of time benefits that were sustained for 6 to 12 months. They also rarely increase the dose due to diminished efficacy.18 found that using relaxation therapy in conjunction with However, the potential exists for patients to develop a cognitive therapy frequently reduced the need for medica- physical dependence on benzodiazepines and withdrawal tions and produced the greatest degree of benefit among symptoms upon discontinuation, especially if the discon- compared psychotherapies. A review of studies by Fisher tinuation is abrupt.12 and Durham8 found recovery rates at a 6-month follow-up between 50% and 60% among patients treated with CBT Buspirone or applied relaxation. Using psychotherapy and pharmaco- The azapirone class of medications, which includes bu- therapy in conjunction has shown potential as a treatment spirone, is pharmacologically and structurally distinct of depression,9 so it is possible that a similar strategy may from the benzodiazepines, but, like the benzodiazepines, also be effective in the treatment of GAD. possesses anxiolytic properties. Although the mechanisms of action of the azapirones are incompletely understood, it PHARMACOTHERAPIES has been hypothesized that they function through a reduc- tion of the firing of serotonin-affected nerve fibers by In addition to psychotherapies, physicians have at their means of presynaptic serotonin agonism.19 disposal numerous effective pharmacologic treatments. Among patients with GAD, buspirone has been associ- Recently developed drugs have been shown to be not only ated with reductions in levels of anxiety comparable to more effective than placebo, but also safer and more toler- reductions associated with benzodiazepines.20–24 Despite able than the older medications such as benzodiazepines. comparable efficacy, buspirone tends to have a slower on- Also, current research into the biological mechanisms of set of action than benzodiazepines, often taking 2 weeks GAD is beginning to be converted into potential future or more to manifest efficacy.20–24 Buspirone, unlike benzo- therapies. diazepines, affects the cognitive aspects of GAD15 but does not impair cognitive or psychomotor function or Benzodiazepines induce sedation, muscle relaxation, or withdrawal syn- Benzodiazepines have been used since the 1960s drome.17,19 However, buspirone has been associated with because of their anxiolytic, anticonvulsant, and muscle adverse effects such as dizziness, headache, and nausea.19 relaxant properties.