American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. American Psychiatric Association, Arlington, VA, 2013 （DSM-5 精神疾患の診断・統計マニュアル. 高橋三郎、大野裕監訳、医学書院、東京、2014）.
Bridget F Grant, Deborah S Hasin, Frederick S Stinson, Deborah A Dawson, W June Ruan, Risë B Goldstein, Sharon M Smith, Tulshi D Saha, Boji Huang
Prevalence, correlates, co-morbidity, and comparative disability of DSM-IV generalized anxiety disorder in the USA: results from the National Epidemiologic Survey on Alcohol and Related Conditions.
Psychol Med. 2005 Dec;35(12):1747-59. doi: 10.1017/S0033291705006069. Epub 2005 Oct 5.
Abstract/Text
BACKGROUND: This study addressed the prevalences, correlates, co-morbidity and disability of DSM-IV generalized anxiety disorder (GAD) and other psychiatric disorders in a large national survey of the general population, the National Institute on Alcohol Abuse and Alcoholism's (NIAAA) National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). The study presents nationally representative data, for the first time, on prevalence, correlates, co-morbidity, and comparative disability of DSM-IV GAD.
METHOD: Data are taken from a large (n=43093) representative sample of the adult USA population.R: Prevalences of 12-month and lifetime GAD were 2.1% and 4.1%. Being female, middle-aged, widowed/separated/divorced, and low income increased risk, while being Asian, Hispanic, or Black decreased risk. GAD was highly co-morbid with substance use, and other anxiety, mood, and personality disorders. Co-morbidity in GAD was not substantially greater than for most other Axis I and II disorders. Disability and impairment in pure GAD were equivalent to pure mood disorders, but significantly greater than in pure substance use, and other anxiety and personality disorders. Individuals co-morbid for GAD and each mood disorder were more disabled than those with pure forms of GAD or each mood disorder. When co-morbid with GAD, nicotine dependence and other anxiety and personality disorders were not associated with increased disability over that associated with pure GAD, but GAD did show increased disability over that due to each of these disorders in pure form.Conclusions. Associations between GAD and Axis I and II disorders were strong and significant, with variation among specific disorders. Results strongly support GAD as an independent disorder with significant impairment and disability.
越野好文．ユビキタスな全般性不安障害．臨床精神薬理. 2004; 8(5): 757-763.
H U Wittchen, J Hoyer
Generalized anxiety disorder: nature and course.
J Clin Psychiatry. 2001;62 Suppl 11:15-9; discussion 20-1.
Abstract/Text
Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder in the adult population, yet it remains a relatively poorly understood condition. Clinicians may be familiar with the symptoms of enduring excessive worrying, anxiety, and hypervigilance that are characteristic of GAD, but may not necessarily recognize that these are usually symptoms of a distinct psychiatric disorder. Despite changes in diagnostic criteria, estimates of prevalence for GAD are remarkably consistent across epidemiologic studies. Lifetime prevalence in the general population is estimated at 5% (DSM-III and/or DSM-III-R criteria), with rates as high as 10% among women aged 40 years and above, and cross-sectional rates among primary care attenders are about 8%, making GAD the most prevalent anxiety disorder in primary care. The age at onset of GAD differs from that of other anxiety disorders: prevalence rates are low in adolescents and young adults but increase substantially with age. Females are at greater risk than males, and the disorder is correlated with being unemployed or a housewife or having a chronic medical illness. GAD is frequently associated with comorbid depression and other anxiety and somatoform disorders. Significant GAD-specific disability occurs even when comorbidity is not present.
World Health Organization: The ICD-10 Classification of Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. World Health Organization, 1992 （融道男、中根允文、小見山実監訳. ICD-10精神および行動の障害－臨床記述と診断ガイドライン、医学書院、東京、1993;p.349）.
Starcevic V. Anxiety Disorders in Adults. Oxford University Press, Oxford, 2005;pp102-140.
越野好文．全般性不安障害．概念・診断・心理社会的研究．臨床精神医学．2006;35(6): 793-799.
川上憲人．こころの健康についての疫学調査に関する研究．平成16～18年度厚生労働科学研究費補助金（こころの健康科学研究事業）「こころの健康についての疫学調査に関する研究」総合研究報告書．2007; pp1-21.
Risa B Weisberg
Overview of generalized anxiety disorder: epidemiology, presentation, and course.
J Clin Psychiatry. 2009;70 Suppl 2:4-9.
Abstract/Text
Generalized anxiety disorder (GAD) was defined relatively recently, and the diagnostic criteria are still being refined. The essential feature of the disorder has changed from persistent anxiety to excessive worry, and the required symptom duration has changed from 1 month to 6 months. Additionally, exclusion criteria involving permissibility of the diagnosis in children and wording regarding the relationship of GAD with mood disorders have changed. Nosologic controversies still surround the criteria for excessive worry, symptom duration, the relationship between GAD and major depressive disorder, and the required number of associated symptoms. Alterations in the criteria have been suggested, but more research is needed on the validity of these proposed changes. Generalized anxiety disorder appears to be highly prevalent. In the United States, the lifetime prevalence of DSM-IV GAD is estimated to be about 5% and the current prevalence to be about 2% to 3%. The disorder is differentially prevalent across gender and ethnic and social groups. The course of GAD is chronic and can be exacerbated by poor family relationships, comorbid cluster C personality disorders, and comorbid Axis I disorders. Impairment and suicidal ideation are associated with GAD.
Copyright 2009 Physicians Postgraduate Press, Inc.
Ronald C Kessler, Patricia Berglund, Olga Demler, Robert Jin, Kathleen R Merikangas, Ellen E Walters
Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
Arch Gen Psychiatry. 2005 Jun;62(6):593-602. doi: 10.1001/archpsyc.62.6.593.
Abstract/Text
CONTEXT: Little is known about lifetime prevalence or age of onset of DSM-IV disorders.
OBJECTIVE: To estimate lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the recently completed National Comorbidity Survey Replication.
DESIGN AND SETTING: Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using the fully structured World Health Organization World Mental Health Survey version of the Composite International Diagnostic Interview.
PARTICIPANTS: Nine thousand two hundred eighty-two English-speaking respondents aged 18 years and older.
MAIN OUTCOME MEASURES: Lifetime DSM-IV anxiety, mood, impulse-control, and substance use disorders.
RESULTS: Lifetime prevalence estimates are as follows: anxiety disorders, 28.8%; mood disorders, 20.8%; impulse-control disorders, 24.8%; substance use disorders, 14.6%; any disorder, 46.4%. Median age of onset is much earlier for anxiety (11 years) and impulse-control (11 years) disorders than for substance use (20 years) and mood (30 years) disorders. Half of all lifetime cases start by age 14 years and three fourths by age 24 years. Later onsets are mostly of comorbid conditions, with estimated lifetime risk of any disorder at age 75 years (50.8%) only slightly higher than observed lifetime prevalence (46.4%). Lifetime prevalence estimates are higher in recent cohorts than in earlier cohorts and have fairly stable intercohort differences across the life course that vary in substantively plausible ways among sociodemographic subgroups.
CONCLUSIONS: About half of Americans will meet the criteria for a DSM-IV disorder sometime in their life, with first onset usually in childhood or adolescence. Interventions aimed at prevention or early treatment need to focus on youth.
Ronald C Kessler, Wai Tat Chiu, Olga Demler, Kathleen R Merikangas, Ellen E Walters
Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication.
Arch Gen Psychiatry. 2005 Jun;62(6):617-27. doi: 10.1001/archpsyc.62.6.617.
Abstract/Text
BACKGROUND: Little is known about the general population prevalence or severity of DSM-IV mental disorders.
OBJECTIVE: To estimate 12-month prevalence, severity, and comorbidity of DSM-IV anxiety, mood, impulse control, and substance disorders in the recently completed US National Comorbidity Survey Replication.
DESIGN AND SETTING: Nationally representative face-to-face household survey conducted between February 2001 and April 2003 using a fully structured diagnostic interview, the World Health Organization World Mental Health Survey Initiative version of the Composite International Diagnostic Interview.
PARTICIPANTS: Nine thousand two hundred eighty-two English-speaking respondents 18 years and older.
MAIN OUTCOME MEASURES: Twelve-month DSM-IV disorders.
RESULTS: Twelve-month prevalence estimates were anxiety, 18.1%; mood, 9.5%; impulse control, 8.9%; substance, 3.8%; and any disorder, 26.2%. Of 12-month cases, 22.3% were classified as serious; 37.3%, moderate; and 40.4%, mild. Fifty-five percent carried only a single diagnosis; 22%, 2 diagnoses; and 23%, 3 or more diagnoses. Latent class analysis detected 7 multivariate disorder classes, including 3 highly comorbid classes representing 7% of the population.
CONCLUSION: Although mental disorders are widespread, serious cases are concentrated among a relatively small proportion of cases with high comorbidity.
Roselind Lieb, Eni Becker, Carlo Altamura
The epidemiology of generalized anxiety disorder in Europe.
Eur Neuropsychopharmacol. 2005 Aug;15(4):445-52. doi: 10.1016/j.euroneuro.2005.04.010.
Abstract/Text
The objective of this paper is to provide a review on available data to date on the epidemiology of GAD in Europe, and to highlight areas for future research. MEDLINE searches were performed and supplemented by consultations with experts across Europe to identify non-published reports. Despite variations in the design of studies, available data suggest that (a) about 2% of the adult population in the community is affected (12-month prevalence), (b) GAD is one of the most frequent (up to 10%) of all mental disorders seen in primary care, (c) GAD is a highly impairing condition often comorbid with other mental disorders, (d) GAD patients are high utilizers of healthcare resources, and (e) despite the high prevalence of GAD in primary care, its recognition in general practice is relatively low. Marked data deficits are: lack of data from eastern European countries, lack of information about the natural course of GAD in unselected samples, the vulnerability and risk factors involved in the aetiology of GAD and lack of data about adequate and inappropriate treatments in GAD patients as well as the associated and societal costs of GAD.
J Alonso, M C Angermeyer, S Bernert, R Bruffaerts, T S Brugha, H Bryson, G de Girolamo, R Graaf, K Demyttenaere, I Gasquet, J M Haro, S J Katz, R C Kessler, V Kovess, J P Lépine, J Ormel, G Polidori, L J Russo, G Vilagut, J Almansa, S Arbabzadeh-Bouchez, J Autonell, M Bernal, M A Buist-Bouwman, M Codony, A Domingo-Salvany, M Ferrer, S S Joo, M Martínez-Alonso, H Matschinger, F Mazzi, Z Morgan, P Morosini, C Palacín, B Romera, N Taub, W A M Vollebergh, ESEMeD/MHEDEA 2000 Investigators, European Study of the Epidemiology of Mental Disorders (ESEMeD) Project
Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project.
Acta Psychiatr Scand Suppl. 2004;(420):21-7. doi: 10.1111/j.1600-0047.2004.00327.x.
Abstract/Text
OBJECTIVE: To describe the 12-month and lifetime prevalence rates of mood, anxiety and alcohol disorders in six European countries.
METHOD: A representative random sample of non-institutionalized inhabitants from Belgium, France, Germany, Italy, the Netherlands and Spain aged 18 or older (n = 21425) were interviewed between January 2001 and August 2003. DSM-IV disorders were assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview (WMH-CIDI).
RESULTS: Fourteen per cent reported a lifetime history of any mood disorder, 13.6% any anxiety disorder and 5.2% a lifetime history of any alcohol disorder. More than 6% reported any anxiety disorder, 4.2% any mood disorder, and 1.0% any alcohol disorder in the last year. Major depression and specific phobia were the most common single mental disorders. Women were twice as likely to suffer 12-month mood and anxiety disorders as men, while men were more likely to suffer alcohol abuse disorders.
CONCLUSION: ESEMeD is the first study to highlight the magnitude of mental disorders in the six European countries studied. Mental disorders were frequent, more common in female, unemployed, disabled persons, or persons who were never married or previously married. Younger persons were also more likely to have mental disorders, indicating an early age of onset for mood, anxiety and alcohol disorders.
Hans-Ulrich Wittchen, Ron C Kessler, Katja Beesdo, Petra Krause, Michael Höfler, Jürgen Hoyer
Generalized anxiety and depression in primary care: prevalence, recognition, and management.
J Clin Psychiatry. 2002;63 Suppl 8:24-34.
Abstract/Text
AIMS: Determine attitudes toward patients with generalized anxiety disorder (GAD) and major depressive episodes (MDE) in primary care; determine prevalence of GAD, MDE, and comorbid GAD/MDE among primary care patients; assess physician recognition of GAD and MDE; and describe primary care interventions for these patients.
METHOD: 558 primary care physicians participated in a 1-day survey. Over 20,000 patients completed a diagnostic-screening questionnaire for GAD and MDE. Physician questionnaires included a standardized clinical appraisal of somatic and psychosocial symptoms and information on past and current treatments and a prestudy questionnaire assessing experience with and attitudes toward patients with GAD and MDE.
RESULTS: 56.9% of physicians viewed GAD as a genuine mental disorder with clinical management problems and considerable patient burden; 27.4% treated GAD patients differently from MDE patients. 5.3% of patients met criteria for GAD, 6.0% for MDE, 3.8% for pure GAD, 4.4% for pure MDE, and 1.6% for comorbid GAD/MDE. Pure GAD and MDE were associated with disability, high utilization of health care resources, and suicidality, which were even higher with comorbid GAD/MDE. Physicians recognized clinically significant emotional problems in 72.5% of patients with pure GAD, 76.5% with pure MDE, and 85.4% with comorbid GAD/MDE. However, correct diagnosis was much lower (64.3% for MDE and 34.4% for GAD). Although the majority of patients with recognized GAD or MDE were treated, only a small minority with GAD were prescribed medications or referred to specialists.
CONCLUSION: The high proportion of respondents with pure GAD is inconsistent with previous reports that GAD is usually comorbid with depression. GAD remains poorly recognized and inadequately treated. Improving the recognition and treatment of GAD in primary care patients is discussed relative to new treatments.
越野好文：不安障害．村崎光邦監修：Step up MR Course「中枢神経」．エルゼビア・ジャパン, 東京; 2004; 106-128.
Larry Culpepper
Generalized anxiety disorder and medical illness.
J Clin Psychiatry. 2009;70 Suppl 2:20-4.
Abstract/Text
Patients with generalized anxiety disorder (GAD) often have multiple medical comorbidities. The adrenal system and genetic and environmental factors are intermediaries between anxiety and medical illnesses such as chronic pain conditions and gastrointestinal, cardiovascular, endocrine, and respiratory disorders. Medical disorders associated with anxiety include migraine, rheumatoid arthritis, peptic ulcer disease, irritable bowel syndrome, coronary heart disease, hyperthyroidism, diabetes, asthma, and chronic obstructive pulmonary disorder. Compared to people with pain conditions without GAD, individuals with pain conditions and GAD experience and register pain differently; they also have increased awareness of symptoms. Comorbid medical illnesses may influence treatment choice for GAD. Treatment of anxiety in young patients with GAD needs to be long-term to decrease vulnerability to medical conditions.
Copyright 2009 Physicians Postgraduate Press, Inc.
Lachlan A McWilliams, Renee D Goodwin, Brian J Cox
Depression and anxiety associated with three pain conditions: results from a nationally representative sample.
Pain. 2004 Sep;111(1-2):77-83. doi: 10.1016/j.pain.2004.06.002.
Abstract/Text
Investigations of the relationship between pain conditions and psychopathology have largely focused on depression and have been limited by the use of non-representative samples (e.g. clinical samples). The present study utilized data from the Midlife Development in the United States Survey (MIDUS) to investigate associations between three pain conditions and three common psychiatric disorders in a large sample (N = 3,032) representative of adults aged 25-74 in the United States population. MIDUS participants provided reports regarding medical conditions experienced over the past year including arthritis, migraine, and back pain. Participants also completed several diagnostic-specific measures from the Composite International Diagnostic Interview-Short Form [Int. J. Methods Psychiatr. Res. 7 (1998) 171], which was based on the revised third edition of the Diagnostic and Statistical Manual of Mental Disorders [American Psychiatric Association 1987]. The diagnoses included were depression, panic attacks, and generalized anxiety disorder. Logistic regression analyses revealed significant positive associations between each pain condition and the psychiatric disorders (Odds Ratios ranged from 1.48 to 3.86). The majority of these associations remained statistically significant after adjusting for demographic variables, the other pain conditions, and other medical conditions. Given the emphasis on depression in the pain literature, it was noteworthy that the associations between the pain conditions and the anxiety disorders were generally larger than those between the pain conditions and depression. These findings add to a growing body of evidence indicating that anxiety disorders warrant further attention in relation to pain. The clinical and research implications of these findings are discussed.
Renee D Goodwin, Murray B Stein
Generalized anxiety disorder and peptic ulcer disease among adults in the United States.
Psychosom Med. 2002 Nov-Dec;64(6):862-6.
Abstract/Text
OBJECTIVE: Previous research has suggested a link between chronic anxiety and peptic ulcer disease, though recent evidence documenting an infectious cause (Helicobacter pylori) for ulcer has led to doubt about this association. The goal of the current study was to determine the relationship between generalized anxiety disorder (GAD) and self-reported peptic ulcer disease (PUD) among adults in the community.
METHODS: Data were drawn from the National Comorbidity Survey, a representative household survey of the adult population of the United States (N = 8098). Multivariate logistic regression analyses were used to determine the relationship between GAD and self-reported ulcer, controlling for differences in sociodemographic characteristics and psychiatric and medical comorbidity.
RESULTS: GAD was associated with a significantly increased risk of self-reported PUD (odds ratio = 2.8, 95% confidence interval = 1.4-5.7; p = .0002) after adjusting for differences in sociodemographic characteristics, comorbid mental disorders, and physical morbidity. Further analyses revealed a dose-response relationship between number of GAD symptoms (odds ratio = 1.2, 95% confidence interval = 1.1-1.4; p = .001) and increased risk of self-reported PUD.
CONCLUSIONS: These findings are consistent with and extend previous clinical and epidemiologic data, providing evidence of a dose-response relationship between GAD and self-reported PUD among adults in the general population. The mechanism of this association remains unknown. Future work investigating the relationship between onset of GAD and development of PUD in prospective, longitudinal, epidemiologic data with objective measures of physical health status and mental health may be useful in improving our understanding of this link.
Martin C Härter, Kevin P Conway, Kathleen R Merikangas
Associations between anxiety disorders and physical illness.
Eur Arch Psychiatry Clin Neurosci. 2003 Dec;253(6):313-20. doi: 10.1007/s00406-003-0449-y.
Abstract/Text
OBJECTIVE: In contrast to the literature on the association of depression with medical illness, less is known about the comorbidity among anxiety and somatic disorders. Although associations between anxiety disorders and medical illnesses have been reported, prior studies have not adjusted for the effects of gender, substance abuse/dependence, and depression. This study examined the patterns of comorbidity of anxiety disorders and physical illnesses.
METHOD: A total of 262 probands were selected from treatment settings or were randomly recruited from the community. DSM-III-R diagnoses were obtained based on direct interview (SADS) or family history information, and lifetime history of numerous medical illnesses were obtained.
RESULTS: Patients with a lifetime anxiety disorder reported higher rates of several medical illnesses than did persons without anxiety. After controlling for the effects of gender, comorbid substance abuse/dependence and/or depression, significant associations were found between anxiety disorder and cardiac disorders (OR = 4.6), hypertension (OR = 2.4), gastrointestinal problems (OR = 2.4), genitourinary disorders (OR = 3.5), and migraine (OR = 5.0). A similar pattern was observed for probands with panic or generalized anxiety disorder (GAD).
CONCLUSIONS: Anxiety disorders were associated with a specific pattern of cardiac disorders, hypertension, gastrointestinal problems, genitourinary difficulties, and migraine; individuals presenting with anxiety disorders or medical illness need therefore to be evaluated carefully for comorbidity.
Nicoletta Sonino, Cecilia Navarrini, Chiara Ruini, Fedra Ottolini, Agostino Paoletta, Francesco Fallo, Marco Boscaro, Giovanni A Fava
Persistent psychological distress in patients treated for endocrine disease.
Psychother Psychosom. 2004 Mar-Apr;73(2):78-83. doi: 10.1159/000075538.
Abstract/Text
BACKGROUND: The purpose of the study was to assess the frequency and characteristics of psychological distress, even after adequate treatment, in the heterogeneous population of an endocrine outpatient clinic.
METHODS: 146 endocrine patients (31 males/115 females; age 39.4 +/- 12.5 years), who were cured or in remission, were studied in a university endocrine outpatient clinic. Semistructured clinical interviews to assess psychiatric (Structured Clinical Interview for DSM-IV) and psychological (Diagnostic Criteria for Psychosomatic Research, DCPR) diagnoses were employed and were supplemented by self-rated instruments (the Psychosocial Index and the Medical Outcome Study short form General Health Survey) which could provide the patients' perception of their own quality of life.
RESULTS: There were 118 patients (81%) who presented with at least 1 psychiatric (DSM-IV) or psychological (DCPR) diagnosis. The most frequent diagnostic findings were generalized anxiety disorder (29%), major depression (26%), irritable mood (46%), demoralization (34%) and persistent somatization (21%). By self-rated instruments, patients with at least 1 DSM-IV or DCPR diagnosis reported significantly more stressful life circumstances, psychological distress and an impaired quality of life compared to those who had none.
CONCLUSIONS: A high prevalence of psychological distress may be encountered in the long-term follow-up of endocrine patients. A biopsychosocial consideration of the person and his/her quality of life appears to be mandatory for improving therapeutic effectiveness in endocrine disorders.
Copyright 2004 S. Karger AG, Basel
Naomi M Simon, Deborah Blacker, Nicole B Korbly, Saumya G Sharma, John J Worthington, Michael W Otto, Mark H Pollack
Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review.
J Affect Disord. 2002 May;69(1-3):209-17.
Abstract/Text
BACKGROUND: The need for thyroid screening of patients presenting with panic disorder (PD), social phobia (SP) or generalized anxiety disorder (GAD) remains uncertain.
METHODS: We examined thyroid histories and serum testing in 169 patients, 92 with PD, 48 with SP, and 29 with GAD. Combined prevalence rates of hyperthyroidism and hypothyroidism were compared with expected rates (2.7%) derived from the population based Whickham Survey. Data from previously published studies were also compared with these expected rates.
RESULTS: In our sample, only 2/169 patients had thyroid dysfunction detected by serum testing, but 5/169 [1/92 (1%) with PD, 1/48 (2%) with SP, and 3/29 (10%) with GAD], all currently euthyroid, reported a history of thyroid disease. The rates were statistically significant only for GAD (10.4%; z = 2.56, p = 0.01). However, combining prior PD studies that examined both thyroid history and test results with our data also suggests significantly elevated rates of thyroid dysfunction (6.5%; z = 4.69, p < 0.0001).
LIMITATIONS: As with previous data, the 95% confidence interval for our findings is broad, reflecting the instability of low rates of illness in relatively small samples. Further, methods for obtaining thyroid histories and tests were not uniform.
CONCLUSIONS: Despite relatively low yields on serum testing, lifetime prevalence of thyroid dysfunction does appear elevated for GAD and PD, with minimal data addressing this issue for SP. The data support the need to query GAD and PD patients regarding thyroid history and perform serum testing in those without prior testing.
Allison B Grigsby, Ryan J Anderson, Kenneth E Freedland, Ray E Clouse, Patrick J Lustman
Prevalence of anxiety in adults with diabetes: a systematic review.
J Psychosom Res. 2002 Dec;53(6):1053-60.
Abstract/Text
BACKGROUND: Anxiety is associated with decreased functioning and quality of life. It may have added importance in diabetes for its potential adverse effects on regimen adherence and glycemic control.
OBJECTIVE: To estimate the prevalence of clinically significant anxiety in adults with diabetes.
RESEARCH DESIGN AND METHODS: MEDLINE and PsycINFO databases and published reference lists were searched to identify studies that determined the prevalence of anxiety in diabetes from threshold scores on self-report measures or from diagnostic interviews. Prevalence was calculated as an aggregate mean weighted by the combined number of subjects in the included studies.
RESULTS: Eighteen studies having a combined population (N) of 4076 (2584 diabetic subjects, 1492 controls) satisfied the inclusion criteria. Most did not adjust for the effects of moderator variables such as gender, and only one was community-based. Generalized anxiety disorder (GAD) was present in 14% of patients with diabetes. The subsyndromal presentation of anxiety disorder not otherwise specified and of elevated anxiety symptoms were found in 27% and 40%, respectively, of patients with diabetes. The prevalence of elevated symptoms was significantly higher in women compared to men (55.3% vs. 32.9%, P<.0001) and similar in patients with Type 1 vs. Type 2 diabetes (41.3% vs. 42.2%, P=.80).
CONCLUSION: GAD is present in 14% and elevated symptoms of anxiety in 40% of patients with diabetes who participate in clinical studies. Additional epidemiological studies are needed to determine the prevalence of anxiety in the broader population of persons with diabetes.
Gretchen A Brenes
Anxiety and chronic obstructive pulmonary disease: prevalence, impact, and treatment.
Psychosom Med. 2003 Nov-Dec;65(6):963-70.
Abstract/Text
OBJECTIVE: This article reviews the prevalence of anxiety disorders in patients with chronic obstructive pulmonary disease (COPD) as well as the impact of comorbid anxiety on quality of life in patients with COPD. Published studies on three types of treatments for anxiety are then reviewed: psychopharmacology, psychotherapy, and pulmonary rehabilitation programs.
MATERIALS AND METHODS: A PubMed search was conducted of the literature from 1966 through 2002 using the keywords anxiety, chronic obstructive pulmonary disease, respiratory diseases, obstructive lung diseases, and pulmonary rehabilitation. Any articles that discussed the prevalence of anxiety symptoms or anxiety disorders among patients with COPD, the impact of anxiety on patients with COPD, or the treatment of anxiety in COPD patients were included in this review.
RESULTS: Anxiety disorders, especially generalized anxiety disorder (GAD) and panic disorder, occur at a higher rate in patients with COPD compared with the general population. Not surprisingly, anxiety has a significant and negative impact on quality of life of COPD patients. Nonetheless, few studies have examined pharmacological, psychotherapeutic, or pulmonary rehabilitation treatments for anxiety disorders in the context of COPD. Trials of nortriptyline, buspirone, and sertraline have been found to reduce symptoms of anxiety. Similarly, cognitive-behavioral programs that focus on relaxation and changes in thinking also produced declines in anxious symptoms. Finally, multicomponent pulmonary rehabilitation programs can also result in reductions in anxious symptoms.
CONCLUSIONS: Studies examining the treatment of anxiety disorders in patients with COPD are promising, yet their efficacy needs to be established. The long-term effects of treatment of anxiety disorders on quality of life of COPD patients have yet to be explored.
First MB, Tasman A. DSM-IV-TR Mental Disorders: Diagnosis, Etiology and Treatment. 1st Edition, Wiley, 2004, 946-969.
Starcevic V. Anxiety Disorders in Adults. Oxford University Press, Oxford, 2005, 102-140.
阿部亮、塩入俊樹．全般性不安障害．今日の精神科治療指針2006．臨床精神医学 2006; 35(増刊号):112-118.
Mark H Pollack
Refractory generalized anxiety disorder.
J Clin Psychiatry. 2009;70 Suppl 2:32-8.
Abstract/Text
Generalized anxiety disorder (GAD) has a lifetime prevalence in the US population of about 5.7%. Typically, GAD begins in early adulthood and tends to have a chronic and persistent course. The disorder frequently presents comorbidly with other conditions, and about 90% of patients with GAD have at least 1 comorbid lifetime psychiatric disorder. Patients with GAD tend to be high users of medical services; the disorder is associated with significant physical as well as psychological symptomatology and impacts health, family relationships, and employment. Pharmacologic and psychosocial treatments are available for GAD. Different side effect profiles, speed of onset of action, and discontinuation requirements of individual drugs need to be taken into account when selecting treatment. Treatment selection should include consideration of comorbidity, psychological function, social impairment, and refractoriness, as well as the need for ongoing intervention for many individuals. Innovative treatments, including anticonvulsants, atypical antipsychotics, and others, as well as treatment targeting concomitant insomnia, may help improve outcomes for affected individuals.
Copyright 2009 Physicians Postgraduate Press, Inc.
R B Hidalgo, J R Davidson
Generalized anxiety disorder. An important clinical concern.
Med Clin North Am. 2001 May;85(3):691-710.
Abstract/Text
GAD is common, often follows a chronic course, and usually is associated with extensive psychiatric and medical comorbidity. This disorder often presents in a primary care setting, commonly with somatic symptoms; it is important for primary care physicians to be aware of its existence, forms of presentation, and different treatments. GAD appears to be twice as common in women than men. There is some evidence that the neurobiologic basis of GAD may involve abnormalities in neurochemical, neuroendocrine, neurophysiologic, and neuroanatomic factors. Research on psychosocial treatment of GAD has favored the combination of cognitive therapy and relaxation techniques or anxiety management training. It also appears that relapse rates after termination of cognitive-behavioral therapy are low. Taking into consideration that GAD generally is chronic and associated frequently with depressive symptoms, the ideal pharmacotherapy may be a drug that can treat these comorbid disorders adequately. New antidepressants, especially those with action in the serotonin system and possibly noradrenergic, may be the appropriate option: They not only treat anxiety, but also treat or prevent the development of comorbid depression; they should be effective ideally during prolonged periods without risks related to addiction or withdrawal, such as may happen with benzodiazepines and some antidepressants. The role of newly emerging drugs, such as some anticonvulsants, in GAD needs to be defined more clearly. More research is warranted to address issues such as (1) whether pharmacotherapy is as effective, less effective, or more effective than cognitive-behavioral therapy; (2) whether antidepressants improve the rate of wellness or remission; and (3) whether prolonged antidepressant therapy for GAD protects against later emergent depression.
J C Ballenger, J R Davidson, Y Lecrubier, D J Nutt, T D Borkovec, K Rickels, D J Stein, H U Wittchen
Consensus statement on generalized anxiety disorder from the International Consensus Group on Depression and Anxiety.
J Clin Psychiatry. 2001;62 Suppl 11:53-8.
Abstract/Text
OBJECTIVE: To provide primary care clinicians with a better understanding of management issues in generalized anxiety disorder (GAD) and guide clinical practice with recommendations on the appropriate treatment strategy.
PARTICIPANTS: The 4 members of the International Consensus Group on Depression and Anxiety were James C. Ballenger (chair), Jonathan R.T. Davidson, Yves Lecrubier, and David J. Nutt. Four additional faculty members invited by the chair were Karl Rickels, Hans-Ulrich Wittchen, Dan J. Stein, and Thomas D. Borkovec.
EVIDENCE: The consensus statement is based on the 6 review articles that are published in this supplement and the scientific literature relevant to the issues reviewed in these articles.
CONSENSUS PROCESS: Group meetings were held over a 2-day period. On day 1, the group discussed the review articles and the chair identified key issues for further debate. On day 2, the group discussed these issues to arrive at a consensus view. After the group meetings, the consensus statement was drafted by the chair and approved by all attendees.
CONCLUSIONS: GAD is the most common anxiety disorder in primary care and is highly debilitating. Furthermore, it is frequently comorbid with depression and other anxiety disorders, which exacerbates functional impairment. Antidepressants (serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and nonsedating tricyclic antidepressants) are generally the most appropriate first-line pharmacotherapy for GAD, since they are also effective against comorbid psychiatric disorders and are suitable for long-term use. Cognitive-behavioral therapy is the preferred form of psychotherapy for GAD, although when GAD is comorbid with depression, pharmacotherapy is increasingly indicated.
Monnier J, Brawman-Mintzer O. Generalized anxiety disorder. In: Nutt D, Ballenger J eds. Anxiety Disorders. Blackwell, Oxford. 2003; 51-64.
Lecrubier Y. Risk factors for suicide attempts: epidemiological evidence[abstract]. Eur Neuropsychopharmacol. 1998;8(suppl 1):S114.
World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. World Health Organization, 1992（融道男、中根允文、小見山実監訳：ICD-10精神および行動の障害－臨床記述と診断ガイドライン．医学書院、東京、1993;p349）.
越野好文．不安障害とうつ病．臨床精神医学. 2000;29(8):983-989.
M B Stein, P Kirk, V Prabhu, M Grott, M Terepa
Mixed anxiety-depression in a primary-care clinic.
J Affect Disord. 1995 May 17;34(2):79-84. doi: 10.1016/0165-0327(95)00002-5.
Abstract/Text
To determine the prevalence and clinical significance of a mixed anxiety-depressive (MAD) syndrome in primary care, a two-stage sampling design was applied to 796 consecutive clinic attendees without known psychiatric illness. Among 78 systematically interviewed subjects, 10.3% (n = 8) had a depressive disorder alone, 12.8% (n = 10) had an anxiety disorder alone, 19.2% (n = 15) had a comorbid anxiety and depressive disorder and 12.8% (n = 10) had a combination of subsyndromal anxiety and depressive features that fulfilled either ICD-10 or our own operational criteria for MAD. Patients with MAD rated their disability as being comparable to that of patients with anxiety or depressive disorders. These findings lend support to the notion that there is a sizeable subgroup of patients in primary care who appear to be suffering from a psychiatric syndrome with an admixture of subsyndromal depressive and anxiety features. Questions about the temporal stability of MAD and preferred approaches to treatment have yet to be answered.
H U Wittchen, C A Essau
Comorbidity and mixed anxiety-depressive disorders: is there epidemiologic evidence?
J Clin Psychiatry. 1993 Jan;54 Suppl:9-15.
Abstract/Text
Recent epidemiologic studies (i.e., studies conducted since 1980) have consistently demonstrated, on the basis of standardized diagnostic assessments, that there is a substantial overlap between different types of anxiety and depressive disorders. The current literature, however, discusses this issue primarily within the concept of comorbidity and there are some controversies about the existence of a separate disorder of mixed anxiety-depression (MAD). MAD can be defined by the presence of mixed symptoms of depression and anxiety that are below the diagnostic threshold for either one of these diagnoses. Since MAD has not been included in any of the current official classification systems, its prevalence, risk factors, course, and outcome have not been studied specifically in any of the recent epidemiologic studies even though MAD is thought to be very important, especially in primary care settings. This paper reviews recent epidemiologic studies and presents data from the Munich Follow-Up Study, which has found a prevalence of about 1% for MAD as defined by the ICD-10. Despite the lack of clear diagnostic criteria for MAD, there are some indications that: (1) this disorder might be frequent in primary care settings, and (2) patients with MAD frequently demonstrate subjective suffering, show impairment in personal and occupational functioning, and have high health service utilization rates. Current empirical evidence is still insufficient for deciding a suitable classificatory solution for this problem.
Naomi M Simon
Generalized anxiety disorder and psychiatric comorbidities such as depression, bipolar disorder, and substance abuse.
J Clin Psychiatry. 2009;70 Suppl 2:10-4.
Abstract/Text
Generalized anxiety disorder (GAD) has a high rate of comorbidity with other psychiatric disorders, including major depressive disorder (MDD), bipolar disorder, other anxiety disorders, and substance use disorders. The similarities between GAD and MDD have led some to suggest that GAD should be reclassified as a mood disorder. The concurrence of GAD with another disorder heightens a patient's risk for impairment, disability, and suicidality. Clinical trials for GAD and disorders that are most likely to occur with GAD have generally not taken comorbidity into account, and there is a paucity of data guiding how comorbidity should inform treatment selection. Research into the biology and psychopathology underlying the high rate of comorbidity of GAD and into efficacious interventions for GAD with comorbidity is needed.
Copyright 2009 Physicians Postgraduate Press, Inc.
Naomi M Simon, Michael W Otto, Stephen R Wisniewski, Mark Fossey, Kemal Sagduyu, Ellen Frank, Gary S Sachs, Andrew A Nierenberg, Michael E Thase, Mark H Pollack
Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
Am J Psychiatry. 2004 Dec;161(12):2222-9. doi: 10.1176/appi.ajp.161.12.2222.
Abstract/Text
OBJECTIVE: The authors provide a detailed perspective on the correlates of comorbid anxiety in a large, well-characterized sample of bipolar disorder patients.
METHOD: Anxiety and its correlates were examined in a cross-sectional sample from the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder.
RESULTS: Lifetime comorbid anxiety disorders were common, occurring in over one-half of the sample, and were associated with younger age at onset, decreased likelihood of recovery, poorer role functioning and quality of life, less time euthymic, and greater likelihood of suicide attempts. Although substance abuse disorders were particularly prevalent among patients with anxiety disorders, comorbid anxiety appeared to exert an independent, deleterious effect on functioning, including history of suicide attempts (odds ratio=2.45, 95% CI=1.4-4.2).
CONCLUSIONS: An independent association of comorbid anxiety with greater severity and impairment in bipolar disorder patients was demonstrated, highlighting the need for greater clinical attention to anxiety in this population, particularly for enhanced clinical monitoring of suicidality. In addition, it is important to determine whether effective treatment of anxiety symptoms can lessen bipolar disorder severity, improve response to treatment of manic or depressive symptoms, or reduce suicidality.
Naomi M Simon, Michael W Otto, Roger D Weiss, Mark S Bauer, Sachiko Miyahara, Stephen R Wisniewski, Michael E Thase, Jane Kogan, Ellen Frank, Andrew A Nierenberg, Joseph R Calabrese, Gary S Sachs, Mark H Pollack, STEP-BD Investigators
Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD.
J Clin Psychopharmacol. 2004 Oct;24(5):512-20.
Abstract/Text
Relatively absent from previous studies of the pharmacotherapy for bipolar disorder is examination of the impact of comorbidity on treatment choices. This has occurred despite the presence of high levels of comorbid anxiety and substance use disorders, and the association of these disorders with severity and course markers of bipolar disorder. In this study, we examined comorbid disorders, identified by structured interviews, and the pharmacotherapy reported at study entry by the first 1000 patients entered into a large, multicenter study of bipolar disorder (Systematic Treatment Enhancement Program for Bipolar Disorder). Our study focused on the degree to which comorbid conditions are linked to the reported use of mood stabilizers deemed "minimally adequate" and the association between specific comorbidities and pharmacotherapy treatment, such as the use of anxiolytics in patients with anxiety disorders. Despite the presence of high levels of comorbidity, the presence of these disorders was only minimally associated with pharmacotherapy. Of the sample of bipolar outpatients, only 59% reported pharmacotherapy use meeting criteria for "minimally adequate" mood stabilizer, regardless of comorbid diagnoses, rapid cycling, or bipolar I or II status. Moreover, the cross-sectional use of "comorbidity-specific" pharmacotherapy for anxiety disorders, substance use disorders, and attention deficit disorder in this outpatient sample of patients with bipolar disorders was limited, suggesting that comorbid conditions in patients with bipolar disorder may be undertreated. Our findings highlight the need for greater clinical guidance and treatment options for patients with bipolar disorder and comorbidity.
Blazer DG, Hughes D, George LK, et al. Generalized anxiety disorder. In: Robins LN, Regier DA, eds: Psychiatric Disorders in America: The Epidemiologic Catchment Area Study. The Free Press, New York, 1991;pp180-203 .
Steven E Bruce, Kimberly A Yonkers, Michael W Otto, Jane L Eisen, Risa B Weisberg, Maria Pagano, M Tracie Shea, Martin B Keller
Influence of psychiatric comorbidity on recovery and recurrence in generalized anxiety disorder, social phobia, and panic disorder: a 12-year prospective study.
Am J Psychiatry. 2005 Jun;162(6):1179-87. doi: 10.1176/appi.ajp.162.6.1179.
Abstract/Text
OBJECTIVE: The authors sought to observe the long-term clinical course of anxiety disorders over 12 years and to examine the influence of comorbid psychiatric disorders on recovery from or recurrence of panic disorder, generalized anxiety disorder, and social phobia.
METHOD: Data were drawn from the Harvard/Brown Anxiety Disorders Research Program, a prospective, naturalistic, longitudinal, multicenter study of adults with a current or past history of anxiety disorders. Probabilities of recovery and recurrence were calculated by using standard survival analysis methods. Proportional hazards regression analyses with time-varying covariates were conducted to determine risk ratios for possible comorbid psychiatric predictors of recovery and recurrence.
RESULTS: Survival analyses revealed an overall chronic course for the majority of the anxiety disorders. Social phobia had the smallest probability of recovery after 12 years of follow-up. Moreover, patients who had prospectively observed recovery from their intake anxiety disorder had a high probability of recurrence over the follow-up period. The overall clinical course was worsened by several comorbid psychiatric conditions, including major depression and alcohol and other substance use disorders, and by comorbidity of generalized anxiety disorder and panic disorder with agoraphobia.
CONCLUSIONS: These data depict the anxiety disorders as insidious, with a chronic clinical course, low rates of recovery, and relatively high probabilities of recurrence. The presence of particular comorbid psychiatric disorders significantly lowered the likelihood of recovery from anxiety disorders and increased the likelihood of their recurrence. The findings add to the understanding of the nosology and treatment of these disorders.
Benjamin F Rodriguez, Risa B Weisberg, Maria E Pagano, Steven E Bruce, Michael A Spencer, Larry Culpepper, Martin B Keller
Characteristics and predictors of full and partial recovery from generalized anxiety disorder in primary care patients.
J Nerv Ment Dis. 2006 Feb;194(2):91-7. doi: 10.1097/01.nmd.0000198140.02154.32.
Abstract/Text
The current study examined the naturalistic course of generalized anxiety disorder (GAD) in a sample of 113 primary care patients across a 2-year period. Initial diagnoses were established using structured clinical interviews according to DSM-IV diagnostic criteria. Results indicated that the majority of patients meeting DSM-IV diagnostic criteria for GAD were still symptomatic to some degree after 2 years of follow-up. Rates of full and partial recovery from GAD, however, were found to be higher than those reported for previous studies of GAD in psychiatric patients. Diagnostic comorbidity, severity of psychosocial impairment, and gender were found to be significantly associated with achieving full or partial recovery from GAD. Psychiatric treatment was not found to be associated with time to full or partial recovery from GAD symptoms, likely due to a treatment-biasing effect. These results underscore that GAD is a chronic and persistent illness in primary care patients.
A O Massion, M G Warshaw, M B Keller
Quality of life and psychiatric morbidity in panic disorder and generalized anxiety disorder.
Am J Psychiatry. 1993 Apr;150(4):600-7.
Abstract/Text
OBJECTIVE: This report examines the impact of panic disorder and/or generalized anxiety disorder on quality of life and the implications of these findings on nosological categories.
METHOD: A total of 357 subjects with a current episode of panic disorder and/or generalized anxiety disorder were diagnosed according to DSM-III-R criteria, using structured clinical interviews, as part of a prospective, naturalistic, longitudinal, multicenter study of a clinical population with anxiety disorders.
RESULTS: There was a high degree of coexistence of anxiety disorders and major depressive disorder. Subjects with generalized anxiety disorder almost universally had other disorders, were the most likely to have at least one other anxiety disorder or major depressive disorder at intake, had the earliest age at onset, and had the worst emotional health rating. Subjects with panic disorder without agoraphobia had the most likelihood of a history of alcohol abuse. Nine percent of the subjects had a history of suicide attempts or gestures.
CONCLUSIONS: The subjects showed significant impairment in quality of life. The highly frequent coexistence of other anxiety disorders with generalized anxiety disorder and the overall lack of differences on many quality of life measures raise questions of nosology, particularly for generalized anxiety disorder.
H U Wittchen, S Zhao, R C Kessler, W W Eaton
DSM-III-R generalized anxiety disorder in the National Comorbidity Survey.
Arch Gen Psychiatry. 1994 May;51(5):355-64.
Abstract/Text
BACKGROUND: Nationally representative general population data are presented on the current, 12-month, and lifetime prevalence of DSM-III-R generalized anxiety disorder (GAD) as well as on risk factors, comorbidity, and related impairments.
METHODS: The data are from the National Comorbidity Survey, a large general population survey of persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States. DSM-III-R GAD was assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview.
RESULTS: Generalized anxiety disorder was found to be a relatively rare current disorder with a current prevalence of 1.6% but was found to be a more frequent lifetime disorder affecting 5.1% of the US population aged 15 to 45 years. Generalized anxiety disorder was twice as common among women as among men. Multivariate logistic regression analysis showed that being older than 24 years, separated, widowed, divorced, unemployed, and a homemaker are significant correlates of GAD. Consistent with studies in treatment samples, we found that GAD was frequently associated with a wide spectrum of other mental disorders, with a lifetime comorbidity among 90.4% of the people who had a history of GAD.
CONCLUSION: Contrary to the traditional view that GAD is a mild disorder, we found that the majority of people with GAD, whether they were comorbid or not, reported substantial interference with their life, a high degree of professional help seeking, and a high use of medication because of their GAD symptoms. Although lifetime GAD is highly comorbid, the proportion of current GAD that is not accompanied by any other current diagnosis is high enough to indicate that GAD should be considered an independent disorder rather than exclusively a residual or prodrome of other disorders.
日本版STAI状態・特性不安、実務教育出版、東京都.
大坪天平、幸田るみ子、高塩理ほか．日本版Hamilton Anxiety Rating Scale-Interview Guideline(HARS-IG)の信頼性・妥当性検討．臨床精神薬理．2005;8:1579-1593.
Robert L Spitzer, Kurt Kroenke, Janet B W Williams, Bernd Löwe
A brief measure for assessing generalized anxiety disorder: the GAD-7.
Arch Intern Med. 2006 May 22;166(10):1092-7. doi: 10.1001/archinte.166.10.1092.
Abstract/Text
BACKGROUND: Generalized anxiety disorder (GAD) is one of the most common mental disorders; however, there is no brief clinical measure for assessing GAD. The objective of this study was to develop a brief self-report scale to identify probable cases of GAD and evaluate its reliability and validity.
METHODS: A criterion-standard study was performed in 15 primary care clinics in the United States from November 2004 through June 2005. Of a total of 2740 adult patients completing a study questionnaire, 965 patients had a telephone interview with a mental health professional within 1 week. For criterion and construct validity, GAD self-report scale diagnoses were compared with independent diagnoses made by mental health professionals; functional status measures; disability days; and health care use.
RESULTS: A 7-item anxiety scale (GAD-7) had good reliability, as well as criterion, construct, factorial, and procedural validity. A cut point was identified that optimized sensitivity (89%) and specificity (82%). Increasing scores on the scale were strongly associated with multiple domains of functional impairment (all 6 Medical Outcomes Study Short-Form General Health Survey scales and disability days). Although GAD and depression symptoms frequently co-occurred, factor analysis confirmed them as distinct dimensions. Moreover, GAD and depression symptoms had differing but independent effects on functional impairment and disability. There was good agreement between self-report and interviewer-administered versions of the scale.
CONCLUSION: The GAD-7 is a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research.
村松公美子：Patient health Questionnaire（PHQ-9, PHQ-15） 日本語版および Generalized Anxiety Disorder -7 日本語版 －up to date－、新潟青陵大学大学院臨床心理学研究（7）2014：35ー39.
T J Meyer, M L Miller, R L Metzger, T D Borkovec
Development and validation of the Penn State Worry Questionnaire.
Behav Res Ther. 1990;28(6):487-95.
Abstract/Text
The present report describes the development of the Penn State Worry Questionnaire to measure the trait of worry. The 16-item instrument emerged from factor analysis of a large number of items and was found to possess high internal consistency and good test-retest reliability. The questionnaire correlates predictably with several psychological measures reasonably related to worry, and does not correlate with other measures more remote to the construct. Responses to the questionnaire are not influenced by social desirability. The measure was found to significantly discriminate college samples (a) who met all, some, or none of the DSM-III-R diagnostic criteria for generalized anxiety disorder and (b) who met criteria for GAD vs posttraumatic stress disorder. Among 34 GAD-diagnosed clinical subjects, the worry questionnaire was found not to correlate with other measures of anxiety or depression, indicating that it is tapping an independent construct with severely anxious individuals, and coping desensitization plus cognitive therapy was found to produce significantly greater reductions in the measure than did a nondirective therapy condition.
A S Zigmond, R P Snaith
The hospital anxiety and depression scale.
Acta Psychiatr Scand. 1983 Jun;67(6):361-70.
Abstract/Text
A self-assessment scale has been developed and found to be a reliable instrument for detecting states of depression and anxiety in the setting of an hospital medical outpatient clinic. The anxiety and depressive subscales are also valid measures of severity of the emotional disorder. It is suggested that the introduction of the scales into general hospital practice would facilitate the large task of detection and management of emotional disorder in patients under investigation and treatment in medical and surgical departments.
保坂隆．うつ病スクリーニングテスト．保坂隆監修．在院日数短縮化をめざして. 星和書店、東京、2002; pp68-72.
中込和幸、牛島定信、大坪天平他：本邦におけるGAD研究会が提唱する『GAD治療手順』臨床精神薬理. 2008;11(8): 1571-1573.
尾鷲登志美．不安．下田和孝(編)．脳とこころのプライマリケア．1．うつと不安．東京: シナジー. 2006;pp394-416.
David S Baldwin, Sarah Waldman, Christer Allgulander
Evidence-based pharmacological treatment of generalized anxiety disorder.
Int J Neuropsychopharmacol. 2011 Jun;14(5):697-710. doi: 10.1017/S1461145710001434. Epub 2011 Jan 7.
Abstract/Text
Generalized anxiety disorder (GAD) is common in community and clinical settings. The associated individual and societal burden is substantial, but many of those who could benefit from treatment are not recognized or treated. This paper reviews the pharmacological treatment of GAD, based on findings of randomized placebo-controlled studies. Particular attention is paid to response rates to acute treatment, treatment tolerability, prediction of response, duration of treatment, and further management of patients who do not respond to initial treatment approaches. On the basis of their proven efficacy and reasonable tolerability in randomized placebo-controlled trials, recent evidence-based guidelines for pharmacological management have recommended initial treatment with either a selective serotonin reuptake inhibitor or a serotonin-norepinephrine reuptake inhibitor, although there is also good evidence for the efficacy of pregabalin and quetiapine. It is difficult to predict reliably which patients will respond well to pharmacological treatment, but response to antidepressants is unlikely if there is no evidence of an onset of effect within 4 wk. The small number of placebo-controlled relapse-prevention studies causes uncertainty about the optimal duration of treatment after a satisfactory initial response, but continuing treatment for at least 12 months is recommended. There have been few investigations of the further management of patients who have not responded to first-line treatment, but switching to another evidence-based treatment, or augmentation approaches may be beneficial.
Jonathan R Davidson
First-line pharmacotherapy approaches for generalized anxiety disorder.
J Clin Psychiatry. 2009;70 Suppl 2:25-31.
Abstract/Text
Many patients with generalized anxiety disorder (GAD) do not receive adequate treatment. Several classes of drugs, including benzodiazepines, azapirones, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, antihistamines, alpha(2)delta Ca++ channel modulators, and atypical antipsychotics are consistently beneficial in patients with GAD. Cognitive therapy is also effective as a first-line treatment. When individualizing treatment, drug dose ranges and side effect profiles need to be considered, as well as the patient's comorbid conditions. Doses may need to be reduced for elderly or medically ill patients or those taking other medications. Doses may need to be increased for refractory cases. Common comorbid conditions with GAD include depression, alcohol or drug abuse, social anxiety disorder, and panic disorder. In patients with significant depression, an antidepressant is more likely to succeed than a benzodiazepine. Generalized anxiety disorder is a chronic illness that requires long-term treatment. Remission is attainable but can take several months, and stopping medication increases the risk of relapse within the first year of initiating treatment.
Copyright 2009 Physicians Postgraduate Press, Inc.
Peter Tyrer, David Baldwin
Generalised anxiety disorder.
Lancet. 2006 Dec 16;368(9553):2156-66. doi: 10.1016/S0140-6736(06)69865-6.
Abstract/Text
Generalised anxiety disorder is a persistent and common disorder, in which the patient has unfocused worry and anxiety that is not connected to recent stressful events, although it can be aggravated by certain situations. This disorder is twice as common in women than it is in men. Generalised anxiety disorder is characterised by feelings of threat, restlessness, irritability, sleep disturbance, and tension, and symptoms such as palpitations, dry mouth, and sweating. These symptoms are recognised as part of the anxiety syndrome rather than independent complaints. The symptoms overlap greatly with those of other common mental disorders and we could regard the disorder as part of a spectrum of mood and related disorders rather than an independent disorder. Generalised anxiety disorder has a relapsing course, and intervention rarely results in complete resolution of symptoms, but in the short term and medium term, effective treatments include psychological therapies, such as cognitive behavioural therapy; self-help approaches based on cognitive behavioural therapy principles; and pharmacological treatments, mainly selective serotonin reuptake inhibitors.
Rosario B Hidalgo, Larry A Tupler, Jonathan R T Davidson
An effect-size analysis of pharmacologic treatments for generalized anxiety disorder.
J Psychopharmacol. 2007 Nov;21(8):864-72. doi: 10.1177/0269881107076996.
Abstract/Text
Generalized anxiety disorder (GAD) is a prevalent and impairing disorder, associated with extensive psychiatric and medical comorbidity and usually characterized by a chronic course. Different drugs have been investigated in GAD; among them are the following: 1) SSRIs: paroxetine, sertraline, fluvoxamine and escitalopram; 2) SNRI1s: venlafaxine; 3) benzodiazepines (BZs): alprazolam, diazepam and lorazepam; 4) azapirones (AZAs): buspirone; 5) antihistamines (AHs): hydroxyzine; 6) pregabalin (PGB); and 7) complementary/alternative medicine (CAM): kava-kava and homeopathic preparation. We conducted an effect size (ES) analysis of 21 double-blind placebo-controlled trials of medications treating DSM-III-R, DSM-IV or ICD-10 GAD using HAM-A change in score from baseline or endpoint score as the main efficacy measure. Literature search was performed using MEDLINE and PsycINFO databases including articles published between 1987 and 2003 and personal communications with investigators and sponsors. comparing all drugs versus placebo, the ES was 0.39. Mean ESs, excluding children, were PGB: 0.50, AH: 0.45, SNRI: 0.42, BZ: 0.38, SSRI: 0.36, AZA: 0.17 and CAM: -0.31. Comparing ES for adults versus children/adolescents (excluding CAM) and conventional drugs versus CAM (excluding children/adolescents) we found significantly higher ES for children/adolescents and for conventional drugs (p < 0.001 and p < 0.01, respectively). No significant differences were found when comparing date of publication, location of site (i.e. US versus other), fixed versus flexible dosing, number of study arms, or number of outcome measures used. Medications varied in the magnitude of their ES, ranging from moderate to poor. Adolescents and children showed a much greater ES compared with adults. Subjects taking CAM had worse outcomes than placebo.
David Baldwin, Robert Woods, Richard Lawson, David Taylor
Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis.
BMJ. 2011 Mar 11;342:d1199. Epub 2011 Mar 11.
Abstract/Text
OBJECTIVE: To appraise the evidence for comparative efficacy and tolerability of drug treatments in patients with generalised anxiety disorder.
DESIGN: Systematic review of randomised controlled trials. Primary Bayesian probabilistic mixed treatment meta-analyses allowed pharmacological treatments to be ranked for effectiveness for each outcome measure, given as percentage probability of being the most effective treatment. Secondary frequentist mixed treatment meta-analyses conducted with random effects model; effect size reported as odds ratio and 95% confidence interval.
DATA SOURCES: Medline, Embase, BIOSIS, PsycINFO, Health Economic Evaluations Database, National Health Service Economic Evaluation Database, and Database of Abstracts of Reviews of Effects via DataStar, and Cochrane Database of Systematic Reviews via Cochrane Library (January 1980 to February 2009). Eligibility criteria Double blind placebo controlled randomised controlled trials; published systematic reviews and meta-analyses of randomised controlled trials. Randomised controlled trials including adult participants (aged ≥ 18) receiving any pharmacological treatment for generalised anxiety disorder. Data abstraction methods Titles or abstracts reviewed initially, followed by review of full text publications for citations remaining after first pass. A three person team conducted screening; an independent reviewer checked a random selection (10%) of articles screened. Data extracted for meta-analysis were also independently reviewed.
MAIN OUTCOME MEASURES: Proportion of participants experiencing ≥ 50% reduction from baseline score on Hamilton anxiety scale (HAM-A) (response), proportion with final HAM-A score ≤ 7 (remission), proportion withdrawing from trial because of adverse events (tolerability).
RESULTS: The review identified 3249 citations, and 46 randomised controlled trials met inclusion criteria; 27 trials contained sufficient or appropriate data for inclusion in the analysis. Analyses compared nine drugs (duloxetine, escitalopram, fluoxetine, lorazepam, paroxetine, pregabalin, sertraline, tiagabine, and venlafaxine). In the primary probabilistic mixed treatment meta-analyses, fluoxetine was ranked first for response and remission (probability of 62.9% and 60.6%, respectively) and sertraline was ranked first for tolerability (49.3%). In a subanalysis ranking treatments for generalised anxiety disorder currently licensed in the United Kingdom, duloxetine was ranked first for response (third across all treatments; 2.7%), escitalopram was ranked first for remission (second across all treatments; 26.7%), and pregabalin was ranked first for tolerability (second across all treatments; 7.7%).
CONCLUSIONS: Though the frequentist analysis was inconclusive because of a high level of uncertainty in effect sizes (based on the relatively small number of comparative trials), the probabilistic analysis, which did not rely on significant outcomes, showed that fluoxetine (in terms of response and remission) and sertraline (in terms of tolerability) seem to have some advantages over other treatments. Among five UK licensed treatments, duloxetine, escitalopram, and pregabalin might offer some advantages over venlafaxine and paroxetine.
P Rocca, V Fonzo, M Scotta, E Zanalda, L Ravizza
Paroxetine efficacy in the treatment of generalized anxiety disorder.
Acta Psychiatr Scand. 1997 May;95(5):444-50.
Abstract/Text
Recently, there has been a renewed interest in alternatives to the benzodiazepines for the treatment of generalized anxiety disorder (GAD). The aim of the present study was to compare the efficacy of paroxetine vs. imipramine and 2'-chlordesmethyldiazepam in 81 patients with a DSM-IV diagnosis of GAD. Approximately two-thirds of the patients who completed the study improved greatly or moderately on all three active drugs. During the first 2 weeks of treatment, 2'-chlordesmethyldiazepam treatment resulted in the greatest improvement in anxiety ratings. Both paroxetine and imipramine treatment resulted in more improvement than 2'-chlordesmethyldiazepam by the fourth week of treatment. Paroxetine and imipramine affect predominantly psychic symptoms, whereas 2'-chlordesmethyldiazepam affects predominantly somatic symptoms. Our results suggest that paroxetine is effective for the treatment of GAD.
越野好文:エビデンスの使い方：不安障害．臨床精神薬理 2003; 6(8): 1027-1034.
越野好文．不安の症状による抗不安薬の使い分け．今月の治療 2005; 13(8): 763-769.
越野好文. Benzodiazepine系抗不安薬vs. 5-HT1A受容体部分作動薬vs. 選択的セロトニン再取り込み阻害薬vs. 三環系抗うつ薬．臨床精神薬理. 2005; 9(12): 2413-2420.
越野好文．Sertralineによる不安障害の治療．臨床精神薬理 2006; 9(9): 1851-1858.
Jack M Gorman
Treating generalized anxiety disorder.
J Clin Psychiatry. 2003;64 Suppl 2:24-9.
Abstract/Text
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 effective pharmacotherapies for patients with GAD include anxiolytic benzodiazepines, buspirone, and antidepressants 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 benzodiazepines, 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.
Moira A Rynn, Olga Brawman-Mintzer
Generalized anxiety disorder: acute and chronic treatment.
CNS Spectr. 2004 Oct;9(10):716-23.
Abstract/Text
Clinical and epidemiological data suggest that generalized anxiety disorder (GAD) is a chronic illness causing patients to suffer for many years leading to significant distress in daily life functioning. The literature suggests the several conclusions. GAD is a disorder in need of appropriate treatment and often has a chronic course with comorbid conditions, such as major depression and other anxiety disorders. Benzodiazepines, while effective anxiolytic agents acutely, when prescribed for >4 weeks cause rebound anxiety and following prolonged therapy may lead to withdrawal symptoms. Antidepressants cause significant anxiety relief compared with placebo and for psychosocial treatment cognitive-behavioral therapy is an efficacious psychosocial treatment. Many GAD patients are in need of long-term medication management. Furthermore, there is limited data for patients diagnosed with GAD the treatment outcome with the combination of medication and psychotherapy both acutely and long-term; how to best sequence these treatments; for those patients who do not meet remission criteria what is the ideal approach for augmentation; and for patients with treatment-refractory GAD the empirical evidence is lacking on medication switching and augmentation strategies. Research is needed in the area of developing treatment strategies for patients suffering from treatment-refractory GAD. There is still an urgent need to explore treatment combinations and duration strategies in the management of patients suffering with GAD.
Wayne K Goodman
Selecting pharmacotherapy for generalized anxiety disorder.
J Clin Psychiatry. 2004;65 Suppl 13:8-13.
Abstract/Text
Selection of appropriate treatment for generalized anxiety disorder (GAD) is influenced by several considerations, including psychiatric comorbidity. Emerging data suggest that GAD has a chronic course and a high comorbidity with depression. Successful treatment can be facilitated by first establishing treatment goals, which include managing acute anxiety and following through to remission. Prevention of GAD recurrence should be the ultimate objective. Many treatments exist to aid in the realization of treatment goals, including benzodiazepines, hydroxyzine, buspirone, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). Some SSRIs and an SNRI have been demonstrated effective in both acute and long-term trials, establishing them as first-line therapies. Benzodiazepines are helpful because of their rapid onset of action and efficacy in somatic and autonomic symptoms of GAD. Other medications in the pipeline include gamma-aminobutyric acid (GABA) modulators, which may have lower abuse potential than currently available agents that act at the GABA receptor; corticotropin-releasing hormone (CRH) antagonists; and pregabalin. The recent realization of the chronic nature of GAD and the recognition of its frequent comorbidity with depression, coupled with data from randomized clinical trials of newer generation agents, should help physicians better diagnose GAD and achieve the goal of bringing patients to full remission.
Stephen B Soumerai, Linda Simoni-Wastila, Cara Singer, Connie Mah, Xiaming Gao, Carl Salzman, Dennis Ross-Degnan
Lack of relationship between long-term use of benzodiazepines and escalation to high dosages.
Psychiatr Serv. 2003 Jul;54(7):1006-11.
Abstract/Text
OBJECTIVE: The objective of this study was to determine whether long-term benzodiazepine use is associated with dose escalation.
METHODS: The authors examined changes in dose and the frequency of dose escalation among new and continuing (at least two years) recipients of benzodiazepines identified from a database containing drug-dispensing and health care use data for all New Jersey Medicaid patients for 39 months. Independent variables included age; Medicaid eligibility category; gender; race or ethnicity; neighborhood socioeconomic variables; chronic illnesses, such as schizophrenia, bipolar illness, panic disorder, and seizure disorder; and predominant benzodiazepine received. Logistic regression analyses were conducted to determine the association between the independent variables and escalation to a high dosage (at least 20 diazepam milligram equivalents [DMEs] per day for elderly patients and at least 40 DMEs per day for younger patients).
RESULTS: A total of 2,440 patients were identified, comprising 460 new and 1,980 continuing recipients. Seventy-one percent of continuing recipients had a permanent disability. Among all groups of continuing recipients, the median daily dosage remained constant at 10 DMEs during two years of continuous use. No clinically or statistically significant changes in dosage were observed over time. The incidence of escalation to a high dosage was 1.6 percent. Subgroups with a higher risk of dose escalation included antidepressant recipients and patients who filled duplicate prescriptions for benzodiazepines at different pharmacies within seven days. Elderly and disabled persons had a lower risk of dose escalation than younger patients.
CONCLUSION: The results of this study did not support the hypothesis that long-term use of benzodiazepines frequently results in notable dose escalation.
M H Lader
Limitations on the use of benzodiazepines in anxiety and insomnia: are they justified?
Eur Neuropsychopharmacol. 1999 Dec;9 Suppl 6:S399-405.
Abstract/Text
The benzodiazepines are still extensively used in psychiatry, neurology and medicine in general. Anxiety disorder and severe insomnia are important syndromal indications, but these drugs are widely prescribed at the symptomatic level, resulting in potential overuse. The official data sheets recommend short durations of usage and conservative dosage. Although short-term efficacy is established, long-term efficacy remains controversial, as relevant data are scanty and relapse, rebound and dependence on withdrawal not clearly distinguished. The risks of the benzodiazepines are well-documented and comprise psychological and physical effects. Among the former are subjective sedation, paradoxical release of anxiety and/or hostility, psychomotor impairment, memory disruption, and risks of accidents. Physical effects include vertigo, dysarthria, ataxia with falls, especially in the elderly. Dependence can supervene on long-term use, occasionally with dose escalation. The benzodiazepines are now recognised as major drugs of abuse and addiction. Other drug and non-drug therapies are available and have a superior risk benefit ratio in long-term use. It is concluded that benzodiazepines should be reserved for short-term use--up to 4 weeks--and in conservative dosage.
J H Woods, J L Katz, G Winger
Use and abuse of benzodiazepines. Issues relevant to prescribing.
JAMA. 1988 Dec 16;260(23):3476-80.
Abstract/Text
J Ishigooka, T Sugiyama, M Suzuki, K Kobayashi, H Takeuchi, M Murasaki
Survival analytic approach to long-term prescription of benzodiazepine hypnotics.
Psychiatry Clin Neurosci. 1998 Oct;52(5):541-5. doi: 10.1046/j.1440-1819.1998.00422.x.
Abstract/Text
Eight hundred and sixty-two patients who visited the department of neuropsychiatry and who were prescribed benzodiazepine (BZ) hypnotics were investigated to evaluate the actual state of their use, in terms of age, gender, diagnostic categories according to ICD-9, duration of prescription and dose equivalent to diazepam prescribed. The frequency of prescriptions in subjects were surveyed using Kaplan-Meier survival analysis at every 3 months. Mean survival time to discontinuation was 8.5 months. A total of 60% of the subjects did not receive BZ hypnotics at the end of the third month, but 20% remained to be prescribed after 1 year. Moreover, 7.9% of the subjects were prescribed BZ hypnotics even after 3 years. The results indicated that 20% of patients who had started prescriptions for BZ hypnotics had the potential to induce dependence. The following variables were found in the long-term prescription: male patients; aged patients over 60; and affective psychoses (which mainly consisted of depression) including neurotic depression, in the present study. A low dose was considered to be associated with an ability to be free from BZ hypnotics in an early period.
First MB, Tasman A. DSM-IV-TRTM Mental Disorders. Diagnosis, Etiology & Treatment. Wiley, Chichester, 2004; pp946-969.
R B Lydiard
An overview of generalized anxiety disorder: disease state--appropriate therapy.
Clin Ther. 2000;22 Suppl A:A3-19; discussion A20-4.
Abstract/Text
OBJECTIVE: This article reviews the prevalence, diagnosis, and treatment of generalized anxiety disorder (GAD).
BACKGROUND: Patients with GAD often present to primary care physicians; frequently the disorder manifests with somatic symptoms that have no identifiable physiologic foundation. Accurate diagnosis and treatment often prove elusive, and health care resources are inappropriately consumed in the management of a wide array of complaints, including headache, noncardiac angina, fatigue, insomnia, or abdominal discomfort. Early diagnosis and intervention are critical; GAD is frequently associated with other anxiety and mood disorders, major depressive disorder among them. The differential diagnosis of GAD is complex, including medication side effects and substance-related dependence or withdrawal phenomena, as well as endocrine, neurologic, cardiorespiratory, and autoimmune disorders.
CONCLUSIONS: GAD is differentiated from adjustment disorder with anxiety because only GAD can manifest without identifiable emotional stressors; it is differentiated from panic disorder largely on the basis of the chronicity of GAD and the episodic, abrupt nature of panic attacks, with the involvement of at least 4 autonomic, cardiopulmonary, neurologic, or other symptoms. In addition to psychotherapy, education, lifestyle modifications, and social support, several pharmacologic agents may be appropriate therapy for GAD. Given the chronic, nonremitting, relapsing character of GAD, use of benzodiazepines, which confer short-term relief, is usually ill-advised in long-term treatment because these agents can impair cognitive and psychomotor function, interact with various central nervous system depressants (eg, alcohol), and exhibit substantial potential for abuse, tolerance, dependence, and withdrawal effects. Buspirone and certain antidepressants, including the dual noradrenergic-serotonergic reuptake inhibitor venlafaxine, represent first-line therapy for GAD.
Gould RA, Otto MW, Pollack MH, et al. Cognitive-behavioral and pharmacological treatment of general anxiety disorder: a preliminary meta analysis. Behavior Ther. 1977;28: 285-305, 1997.
T D Borkovec, A M Ruscio
Psychotherapy for generalized anxiety disorder.
J Clin Psychiatry. 2001;62 Suppl 11:37-42; discussion 43-5.
Abstract/Text
The present article describes the basic therapeutic techniques used in the cognitive-behavioral therapy (CBT) of generalized anxiety disorders and reviews the methodological characteristics and outcomes of 13 controlled clinical trials. The studies in general display rigorous methodology, and their outcomes are quite consistent. CBT has been shown to yield clinical improvements in both anxiety and depression that are superior to no treatment and nonspecific control conditions (and at times to either cognitive therapy alone or behavioral therapy alone) at both posttherapy and follow-up. CBT is also associated with low dropout rates, maintained long-term improvements, and the largest within-group and between-group effect sizes relative to all other comparison conditions.
D Westen, K Morrison
A multidimensional meta-analysis of treatments for depression, panic, and generalized anxiety disorder: an empirical examination of the status of empirically supported therapies.
J Consult Clin Psychol. 2001 Dec;69(6):875-99.
Abstract/Text
The authors report a meta-analysis of high-quality studies published from 1990-1998 on the efficacy of manualized psychotherapies for depression, panic disorder, and generalized anxiety disorder (GAD) that bear on the clinical utility and external validity of empirically supported therapies. The results suggest that a substantial proportion of patients with panic improve and remain improved; that treatments for depression and GAD produce impressive short-term effects: that most patients in treatment for depression and GAD do not improve and remain improved at clinically meaningful follow-up intervals: and that screening procedures used in many studies raise questions about generalizability, particularly in light of a systematic relation across studies between exclusion rates and outcome. The data suggest the importance of reporting, in both clinical trials and meta-analyses, a range of outcome indices that provide a more comprehensive, multidimensional portrait of treatment effects and their generalizability. These include exclusion rates, percent improved, percent recovered, percent who remained improved or recovered at follow-up, percent seeking additional treatment at follow-up, and data on both completer and intent-to-treat samples.
Roger Covin, Allison J Ouimet, Pamela M Seeds, David J A Dozois
A meta-analysis of CBT for pathological worry among clients with GAD.
J Anxiety Disord. 2008;22(1):108-16. doi: 10.1016/j.janxdis.2007.01.002. Epub 2007 Feb 3.
Abstract/Text
Previous meta-analyses assessing the effectiveness of Cognitive Behavioural Therapy (CBT) for Generalized Anxiety Disorder (GAD) used general measures of anxiety to assess symptom severity and improvement (e.g., Hamilton Anxiety Ratings Scale or a composite measure of anxiety). While informative, these studies do not provide sufficient evidence as to whether CBT significantly reduces the cardinal symptom of GAD: pathological worry. The current meta-analysis employed stringent inclusion criteria to evaluate relevant outcome studies, including the use of the Penn State Worry Questionnaire as the main outcome variable. Results showed a large overall effect size (ES) that was moderated by age and modality of treatment. Specifically, the largest gains were found for younger adults and for individual treatment. Analyses also revealed overall maintenance of gains at 6- and 12-month follow-up. Clinical implications of different treatment packages are discussed, as well as potential explanations for the differential effectiveness of CBT.
J Joormann, J Stöber
Somatic symptoms of generalized anxiety disorder from the DSM-IV: associations with pathological worry and depression symptoms in a nonclinical sample.
J Anxiety Disord. 1999 Sep-Oct;13(5):491-503.
Abstract/Text
The present study investigates specificity of the six somatic symptoms that are associated with generalized anxiety disorder (GAD), according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. A nonclinical sample of 183 students provided severity ratings for (a) restlessness, (b) easily fatigued, (c) difficulty concentrating, (d) irritability, (e) muscle tension, and (f) sleep disturbance. In addition, they responded to questionnaires assessing pathological worry and depression symptoms. Partial correlations and multiple regression analyses indicated that only muscle tension showed a unique relation to pathological worry. In contrast, difficulty concentrating was exclusively related to depression symptoms. Present findings corroborate psychophysiological findings that elevated muscle tension is a specific characteristic of pathological worriers. Moreover, they suggest that the problem of unclear boundaries between GAD and major depression may be reduced if future revisions of the somatic symptom list for GAD emphasize muscle tension while de-emphasizing difficulty concentrating.
Michael Pluess, Ansgar Conrad, Frank H Wilhelm
Muscle tension in generalized anxiety disorder: a critical review of the literature.
J Anxiety Disord. 2009 Jan;23(1):1-11. doi: 10.1016/j.janxdis.2008.03.016. Epub 2008 Apr 7.
Abstract/Text
BACKGROUND: Generalized anxiety disorder (GAD) is a prevalent, disabling, and often chronic disorder. With a typical recovery rate of only about 40% with current psychological treatments a better understanding of potential psychophysiological mechanisms is vital.
METHODS: Since the most discriminative somatic symptom of GAD compared to other anxiety disorders is muscle tension this review qualitatively examines the literature on muscle tension as it relates to GAD and muscle relaxation therapy for GAD patients.
RESULTS: Muscle tension in GAD is poorly understood. Experimental studies refute the often-assumed direct relationship between anxiety and muscle tension. However, muscle relaxation therapies have been as effective as cognitive interventions directly addressing the defining symptom worry.
CONCLUSIONS: Muscle tension in its objective and subjective representations may play a role in GAD through various pathways that are testable. Future research needs to better examine the different aspects and functions of muscle tension in GAD.
P L Fisher, R C Durham
Recovery rates in generalized anxiety disorder following psychological therapy: an analysis of clinically significant change in the STAI-T across outcome studies since 1990.
Psychol Med. 1999 Nov;29(6):1425-34.
Abstract/Text
BACKGROUND: There have been six randomized controlled trials of psychological therapy with generalized anxiety disorder (GAD) using DSM-III-R and DSM-IV. All have used the Trait version of the Spielberger State-Trait Anxiety Inventory (STAI-T) as one of several outcome measures. Each study, however, employed different methods of calculating the clinical significance of outcomes making it difficult to reach a balanced appraisal of the efficacy of psychological treatment.
METHODS: Raw data on STAI-T scores at pre-, post- and follow-up were obtained for each of the six studies (total N = 404). Jacobson methodology for defining clinically significant change (criterion c, reliable change index = 8, cut-off point = 46) was used to allocate each patient to one of four outcomes: worse, unchanged, improved and recovered. The proportion of patients in each category was calculated for treatment conditions in each study and also for aggregate data across types of treatment.
RESULTS: A recovery rate of 40% was found for the sample as a whole with 12 of the 20 treatment conditions obtaining very modest recovery rates of 30% or less. Two treatment approaches--individual cognitive behavioural therapy and applied relaxation--do relatively well with overall recovery rates at 6-month follow-up of 50-60%.
CONCLUSIONS: Jacobson methodology, in distinguishing between improvement and recovery on a standardized measure of general vulnerability to anxiety, provides a stringent but clinically more meaningful evaluation of the efficacy of psychological therapies with GAD than has been available hitherto. Systematic focus on either excessive worry or physiological arousal gives worthwhile results.
Miny Samuel, Evelina A Zimovetz, Zahava Gabriel, Stephen M Beard
Efficacy and safety of treatments for refractory generalized anxiety disorder: a systematic review.
Int Clin Psychopharmacol. 2011 Mar;26(2):63-8. doi: 10.1097/YIC.0b013e328341bb4a.
Abstract/Text
This study systematically collated clinical evidence on refractory generalized anxiety disorder (GAD). Refractory GAD patients are those who have failed to respond adequately to at least one earlier treatment for GAD. MEDLINE, EMBASE, The Cochrane Library and conference proceedings were searched to identify trials. Four placebo-controlled trials (pregabalin, olanzapine, quetiapine, risperidone) and four single-arm studies (aripiprazole, risperidone, quetiapine, ziprasidone) evaluated the add-ons to initial treatment(s) or switch of treatment(s) because of inadequate efficacy. The most robust trial was the pregabalin study, with a study duration of 8 weeks and a largest sample size that consists of 356 patients. A significant reduction in the Hamilton Anxiety Scale (HAM-A) score was found for pregabalin and risperidone augmentation compared with placebo. Olanzapine augmentation resulted in a significantly higher proportion of responders (using HAM-A scores) compared with placebo. Quetiapine augmentation did not result in significantly greater mean reductions in the HAM-Ascores compared with placebo. There is a need for effective and safe augmentation treatments for patient's refractory to initial treatments for GAD. This study has located one large robust trial assessing the add-on to pregabalin. All other trials were small and unpowered studies with less than 50 patients. Further high-quality trials of augmentation treatment on refractory GAD are required.
Adjunctive pregabalin treatment after partial response in generalized anxiety disorder: results of a double-blind placebo controlled trial. Presented at the 162nd Annual Meeting of the American Psychiatric Association; San Francisco, CA. May 16-21, 2009.
Naomi M Simon, Kathryn M Connor, Richard T LeBeau, Elizabeth A Hoge, John J Worthington, Wei Zhang, Jonathan R T Davidson, Mark H Pollack
Quetiapine augmentation of paroxetine CR for the treatment of refractory generalized anxiety disorder: preliminary findings.
Psychopharmacology (Berl). 2008 May;197(4):675-81. doi: 10.1007/s00213-008-1087-x. Epub 2008 Feb 2.
Abstract/Text
RATIONALE: More data are needed to guide "next step" strategies for patients with generalized anxiety disorder (GAD) remaining symptomatic despite initial pharmacotherapy.
OBJECTIVE: This study prospectively examined the relative efficacy of quetiapine versus placebo augmentation for individuals with GAD remaining symptomatic with initial paroxetine CR pharmacotherapy.
MATERIALS AND METHODS: Adult outpatients with GAD were recruited from 2004 to 2007 at two academic centers. Phase 1 consisted of 10 weeks of open-label paroxetine CR flexibly dosed to a maximum of 62.5 mg/day. Those remaining symptomatic (Hamilton Anxiety Scale [HAM-A] >or= 7) at week 10 were randomized to quetiapine or placebo augmentation flexibly dosed from 25 to 400 mg/day.
RESULTS: For participants receiving paroxetine CR (n = 50), there was a significant reduction in HAM-A scores (baseline mean +/- SD = 22.4 +/- 4.2 to endpoint mean +/- SD = 11.2 +/- 6.9; paired t = 12.1, df = 49, t < 0.0001) with 40% (n = 20) achieving remission. Counter to our hypothesis, we did not find significant benefit for quetiapine augmentation of continued paroxetine CR (HAM-A reduction mean +/- SD = 2.6 +/- 5.8 points quetiapine, 0.3 +/- 5.5 points placebo; t = 0.98, df = 20, p = n.s.) in the randomized sample (n = 22) with relatively minimal additional improvement overall in phase 2.
CONCLUSIONS: Although conclusions are considered preliminary based on the relatively small sample size, our data do not support the addition of quetiapine to continued paroxetine CR for individuals with GAD who remain symptomatic after 10 weeks of prospective antidepressant pharmacotherapy and suggest that further research examining strategies for GAD refractory to antidepressants is needed.
Mark H Pollack, Naomi M Simon, Alyson K Zalta, John J Worthington, Elizabeth A Hoge, Eric Mick, Gustavo Kinrys, Julia Oppenheimer
Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study.
Biol Psychiatry. 2006 Feb 1;59(3):211-5. doi: 10.1016/j.biopsych.2005.07.005. Epub 2005 Sep 1.
Abstract/Text
BACKGROUND: There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine.
METHODS: Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation.
RESULTS: Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A CONCLUSIONS: Olanzapine may have a salutary effect on anxiety for some GAD patients remaining symptomatic despite initial serotonin selective reuptake inhibitor (SSRI) therapy, but the emergence of significant weight gain represents an important clinical consideration.
Olga Brawman-Mintzer, Rebecca G Knapp, Paul J Nietert
Adjunctive risperidone in generalized anxiety disorder: a double-blind, placebo-controlled study.
J Clin Psychiatry. 2005 Oct;66(10):1321-5.
Abstract/Text
OBJECTIVE: Although significant advances have been made in recent years in the treatment of generalized anxiety disorder (GAD), many patients remain symptomatic despite ongoing treatment, underscoring the need for adjunctive new treatments to help improve response.
METHOD: Forty patients with a primary diagnosis of DSM-IV GAD, who continued to experience GAD symptoms despite current anxiolytic treatment of at least 4 weeks' duration, as evidenced by Hamilton Rating Scale for Anxiety (HAM-A) total score > or = 18 and Clinical Global Impressions-Severity of Illness scale score of moderate or greater, completed a 1-week screening phase and were then randomly assigned to 5 weeks of double-blind adjunctive treatment with placebo or risperidone at flexible doses of 0.5 to 1.5 mg/day. Patients continued to take their anxiolytics throughout the study. The study was conducted from June 2001 through March 2003.
RESULTS: Adjunctive risperidone was associated with statistically significant improvements in core anxiety symptoms, as demonstrated by greater reductions in HAM-A total scores (p = .034) and HAM-A psychic anxiety factor scores (p = .047) compared with placebo. Although change scores on other outcome variables, including response rates, were higher in the risperidone group, differences did not achieve statistical significance.
CONCLUSION: Study findings suggest that risperidone at low doses may represent a useful tool in the management of symptomatic GAD patients.
M A Katzman, M Vermani, L Jacobs, M Marcus, B Kong, S Lessard, W Galarraga, L Struzik, A Gendron
Quetiapine as an adjunctive pharmacotherapy for the treatment of non-remitting generalized anxiety disorder: a flexible-dose, open-label pilot trial.
J Anxiety Disord. 2008 Dec;22(8):1480-6. doi: 10.1016/j.janxdis.2008.03.002. Epub 2008 Mar 13.
Abstract/Text
BACKGROUND: Generalized anxiety disorder (GAD) is a chronic disorder associated with significant morbidity and disability. Traditional therapies are associated with poor levels of remission, and often result in troublesome side effects.
METHODS: This was a 12-week, open-label, flexible-dose study to assess the efficacy and tolerability of quetiapine as an adjunctive treatment to traditional medication. 40 outpatients with GAD who had not achieved remission following at least 8 weeks of an adequate dose of traditional therapy were enrolled. The primary endpoint was the mean change from pre-treatment to week 12 in the Hamilton Anxiety Rating Scale (HAM-A) total scores. Secondary endpoints included: the proportion of patients achieving remission (HAM-A total score of < or =10 at week 12), Clinical Global Impressions-Severity of Illness (CGI-S), Clinical Global Impressions-Global Improvement (CGI-I), Pittsburgh Sleep Quality Index (PSQI) and Penn State Worry Questionnaire (PSWQ).
RESULTS: Adjunctive quetiapine (mean dose 386mg/day at week 12) significantly reduced the HAM-A total scores from pre-treatment (29.8+/-9.0) to week 12 (9.0+/-10.2) (-20.6; p<0.001). The HAM-A remission rate was 72.1% at week 12. Adjunctive quetiapine resulted in a significant reduction in all efficacy measures by study end. Quetiapine was well tolerated: the most common adverse event (AE) was sedation, with no incidence of serious AEs and no clinically significant changes in vital signs, weight (mean gain 0.5kg at week 12) or laboratory assessments.
CONCLUSION: The results of this small pilot trial suggest that quetiapine adjunctive to traditional therapy may be a useful treatment in patients with GAD or treatment-resistant GAD, and warrant further investigation.
Matthew A Menza, Roseanne D Dobkin, Humberto Marin
An open-label trial of aripiprazole augmentation for treatment-resistant generalized anxiety disorder.
J Clin Psychopharmacol. 2007 Apr;27(2):207-10. doi: 10.1097/01.jcp.0000248620.34541.bc.
Abstract/Text
Naomi M Simon, Elizabeth A Hoge, Diana Fischmann, John J Worthington, Kelly M Christian, Gustavo Kinrys, Mark H Pollack
An open-label trial of risperidone augmentation for refractory anxiety disorders.
J Clin Psychiatry. 2006 Mar;67(3):381-5.
Abstract/Text
BACKGROUND: There is a paucity of data to support "next-step" treatments for the many patients with anxiety disorders who remain symptomatic after initial pharmacotherapy.
METHOD: Thirty patients with a primary diagnosis of an anxiety disorder-panic disorder (PD), social anxiety disorder (SAD), or generalized anxiety disorder (GAD)-refractory to initial pharmacotherapy with an adequate (or maximally tolerated) antidepressant and/or benzodiazepine trial of at least 8 weeks' duration prior to study initiation received open-label augmentation with flexibly dosed risperidone for 8 weeks. Participants were diagnosed using the Structured Clinical Interview for DSM-IV.
RESULTS: Risperidone augmentation at a mean +/- SD dose of 1.12 +/- 0.68 mg/day (range, 0.25-3.00 mg/day) resulted in a significant reduction in anxiety symptoms across disorders as measured by the Clinical Global Impressions-Severity of Illness scale and Hamilton Rating Scale for Anxiety (HAM-A) scores and for each disorder-specific primary outcome measure-the Panic Disorder Severity Scale, the Liebowitz Social Anxiety Scale, and HAM-A-in the intent-to-treat sample. Seventy percent (21/30) of participants completed the 8-week trial, with premature discontinuation due primarily to sedation and weight gain.
CONCLUSIONS: Although conclusions are limited by the open-label, relatively brief nature of this trial, our data suggest that augmentation with low-dose risperidone may be a useful option for patients with PD, SAD, or GAD refractory to adequate initial intervention with antidepressants and/or benzodiazepines. Longer-term, controlled safety and efficacy data are needed to understand the place of risperidone augmentation in the algorithm of treatment options for refractory anxiety disorders.
Steven H Snyderman, Moira A Rynn, Karl Rickels
Open-label pilot study of ziprasidone for refractory generalized anxiety disorder.
J Clin Psychopharmacol. 2005 Oct;25(5):497-9.
Abstract/Text
K Rickels, E Schweizer
The clinical course and long-term management of generalized anxiety disorder.
J Clin Psychopharmacol. 1990 Jun;10(3 Suppl):101S-110S.
Abstract/Text
Evidence suggests that generalized anxiety disorder (GAD) has a fairly chronic course marked by significant long-term distress and comorbidity. Research has focused on short-term treatment of GAD, and long-term outcome studies after either short- or long-term treatment have been relatively neglected. The authors discuss the benefits and risks of various drug and nondrug therapies used in the long-term management of generalized anxiety disorder and suggest avenues for future research.
