Anxiety disorders constitute the largest group of mental disorders in most western societies and are a leading cause of disability. The essential features of anxiety disorders are excessive and enduring fear, anxiety or avoidance of perceived threats, and can also include panic attacks. Although the neurobiology of individual anxiety disorders is largely unknown, some generalizations have been identified for most disorders, such as alterations in the limbic system, dysfunction of the hypothalamic–pituitary–adrenal axis and genetic factors. In addition, general risk factors for anxiety disorders include female sex and a family history of anxiety, although disorder-specific risk factors have also been identified. The diagnostic criteria for anxiety disorders varies for the individual disorders, but are generally similar across the two most common classification systems: the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the International Classification of Diseases, Tenth Edition (ICD-10). Despite their public health significance, the vast majority of anxiety disorders remain undetected and untreated by health care systems, even in economically advanced countries. If untreated, these disorders are usually chronic with waxing and waning symptoms. Impairments associated with anxiety disorders range from limitations in role functioning to severe disabilities, such as the patient being unable to leave their home.
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Wittchen, H. U. et al. The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur. Neuropsychopharmacol. 21, 655–679 (2011). Provides the most recent state-of-the-art summary of epidemiological evidence of anxiety disorders and their associated burden in Europe.
Haro, J. M. et al. ROAMER: roadmap for mental health research in Europe. Int. J. Methods Psychiatr. Res. 23 (Suppl. 1), 1–14 (2014).
Christopher, P. & Murray, J. L. Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388, 1659–1724 (2016).
Kessler, R. C., Ruscio, A. M., Shear, K. & Wittchen, H.-U. Epidemiology of anxiety disorders. Curr. Top. Behav. Neurosci. 2, 21–35 (2010). Overviews the prevalence of and risk factors for anxiety disorders.
Beesdo, K., Knappe, S. & Pine, D. S. Anxiety and anxiety disorders in children and adolescents: developmental issues and implications for DSM-V. Psychiatr. Clin. North Am. 32, 483–524 (2009). One of the few available prospective, longitudinal epidemiological studies that provides valid incidence data on anxiety disorders as well as the risk for secondary depression.
Batelaan, N. M., Rhebergen, D., Spinhoven, P., van Balkom, A. J. & Penninx, B. W. J. H. Two-year course trajectories of anxiety disorders: do DSM classifications matter? J. Clin. Psychiatry 75, 985–993 (2014).
Spinhoven, P. et al. Prediction of 6-yr symptom course trajectories of anxiety disorders by diagnostic, clinical and psychological variables. J. Anxiety Disord. 44, 92–101 (2016).
Beesdo, K., Pine, D. S., Lieb, R. & Wittchen, H.-U. Incidence and risk patterns of anxiety and depressive disorders and categorization of generalized anxiety disorder. Arch. Gen. Psychiatry 67, 47–57 (2010).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 5th edn (APA Publishing, 2013).
World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders. WHOhttp://www.who.int/classifications/icd/en/bluebook.pdf (2010).
Kessler, R. C. et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization's World Mental Health Survey Initiative. World Psychiatry 6, 168–176 (2007).
Baxter, A. J., Scott, K. M., Vos, T. & Whiteford, H. A. Global prevalence of anxiety disorders: a systematic review and meta-regression. Psychol. Med. 43, 897–910 (2013).
Lewis-Fernández, R. et al. Culture and the anxiety disorders: recommendations for DSM-V. Depress. Anxiety 27, 212–229 (2010).
Kessler, R. C., Chiu, W. T., Demler, O., Walters, E. E. & Walters, E. E. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch. Gen. Psychiatry 62, 617–627 (2005).
Silove, D. et al. Pediatric-onset and adult-onset separation anxiety disorder across countries in the World Mental Health Survey. Am. J. Psychiatry 172, 647–656 (2015).
Bögels, S. M., Knappe, S. & Clark, L. A. Adult separation anxiety disorder in DSM-5. Clin. Psychol. Rev. 33, 663–674 (2013).
Zhang, X. et al. Generalized anxiety in community-dwelling elderly: prevalence and clinical characteristics. J. Affect. Disord. 172, 24–29 (2015).
Hofmann, S. G. & Hinton, D. E. Cross-cultural aspects of anxiety disorders. Curr. Psychiatry Rep. 16, 450 (2014).
Beesdo-Baum, K. & Knappe, S. Developmental epidemiology of anxiety disorders. Child Adolesc. Psychiatr. Clin. N. Am. 21, 457–478 (2012).
McLean, C. P., Asnaani, A., Litz, B. T. & Hofmann, S. G. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J. Psychiatr. Res. 45, 1027–1035 (2011).
Lieb, R., Isensee, B., Höfler, M., Pfister, H. & Wittchen, H.-U. Parental major depression and the risk of depression and other mental disorders in offspring: a prospective-longitudinal community study. Arch. Gen. Psychiatry 59, 365–374 (2002).
Shimada-Sugimoto, M., Otowa, T. & Hettema, J. M. Genetics of anxiety disorders: genetic epidemiological and molecular studies in humans. Psychiatry Clin. Neurosci. 69, 388–401 (2015).
Otowa, T. et al. Meta-analysis of genome-wide association studies of anxiety disorders. Mol. Psychiatry 21, 1391–1399 (2016). The largest genetic study of mixed anxiety disorders to date. This meta-analysis of anxiety disorders and related symptom scores indicates that the genetic aetiologies of anxiety disorders are similar to those of other common psychiatric disorders, such as depression.
Sareen, J. et al. Adverse childhood experiences in relation to mood and anxiety disorders in a population-based sample of active military personnel. Psychol. Med. 43, 73–84 (2013).
Afifi, T. O., Mota, N. P., Dasiewicz, P., MacMillan, H. L. & Sareen, J. Physical punishment and mental disorders: results from a nationally representative US sample. Pediatrics 130, 184–192 (2012).
Otowa, T., York, T. P., Gardner, C. O., Kendler, K. S. & Hettema, J. M. The impact of childhood parental loss on risk for mood, anxiety and substance use disorders in a population-based sample of male twins. Psychiatry Res. 220, 404–409 (2014).
Taillieu, T. L., Brownridge, D. A., Sareen, J. & Afifi, T. O. Childhood emotional maltreatment and mental disorders: results from a nationally representative adult sample from the United States. Child Abuse Negl. 59, 1–12 (2016).
Vrshek-Schallhorn, S. et al. Validating new summary indices for the Childhood Trauma Interview: associations with first onsets of major depressive disorder and anxiety disorders. Psychol. Assess. 26, 730–740 (2014).
Pérez-Edgar, K. & Fox, N. A. Temperament and anxiety disorders. Child Adolesc. Psychiatr. Clin. N. Am. 14, 681–706 (2005). Provides a detailed overview of the relationship between temperamental factors (which are arguably the single most important risk factor) and anxiety.
Rapee, R. M., Schniering, C. A. & Hudson, J. L. Anxiety disorders during childhood and adolescence: origins and treatment. Annu. Rev. Clin. Psychol. 5, 311–341 (2009).
Greco, L. A. & Morris, T. L. Factors influencing the link between social anxiety and peer acceptance: contributions of social skills and close friendships during middle childhood. Behav. Ther. 36, 197–205 (2005).
Hankin, B. L., Abramson, L. Y., Miller, N. & Haeffel, G. J. Cognitive vulnerability-stress theories of depression: examining affective specificity in the prediction of depression versus anxiety in three prospective studies. Cognit. Ther. Res. 28, 309–345 (2004).
Uliaszek, A. A. et al. A longitudinal examination of stress generation in depressive and anxiety disorders. J. Abnorm. Psychol. 121, 4–15 (2012).
Wittchen, H. U., Kessler, R. C., Pfister, H. & Lieb, M. Why do people with anxiety disorders become depressed? A prospective-longitudinal community study. Acta Psychiatr. Scand. Suppl. 2000, 14–23 (2000).
Beesdo, K. et al. Incidence of social anxiety disorder and the consistent risk for secondary depression in the first three decades of life. Arch. Gen. Psychiatry 64, 903–912 (2007).
Stein, M. B. et al. Social anxiety disorder and the risk of depression: a prospective community study of adolescents and young adults. Arch. Gen. Psychiatry 58, 251–256 (2001).
Zimmermann, P. et al. Primary anxiety disorders and the development of subsequent alcohol use disorders: a 4-year community study of adolescents and young adults. Psychol. Med. 33, 1211–1222 (2003).
Moylan, S., Jacka, F. N., Pasco, J. A. & Berk, M. Cigarette smoking, nicotine dependence and anxiety disorders: a systematic review of population-based, epidemiological studies. BMC Med. 10, 123 (2012).
Phan, K., Xie, A., Di Eusanio, M. & Yan, T. D. A meta-analysis of minimally invasive versus conventional sternotomy for aortic valve replacement. Ann. Thorac. Surg. 98, 1499–1511 (2014).
Kindt, M., Soeter, M. & Vervliet, B. Beyond extinction: erasing human fear responses and preventing the return of fear. Nat. Neurosci. 12, 256–258 (2009).
Etkin, A., Egner, T. & Kalisch, R. Emotional processing in anterior cingulate and medial prefrontal cortex. Trends Cogn. Sci. 15, 85–93 (2011).
LeDoux, J. E. & Pine, D. S. Using neuroscience to help understand fear and anxiety: a two-system framework. Am. J. Psychiatry 173, 1083–1093 (2016).
Etkin, A. & Wager, T. D. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 164, 1476–1488 (2007).
Fanselow, M. S. Neural organization of the defensive behavior system responsible for fear. Psychon. Bull. Rev. 1, 429–438 (1994).
Cuthbert, B. N. & Insel, T. R. Toward the future of psychiatric diagnosis: the seven pillars of RDoC. BMC Med. 11, 126 (2013).
Fonzo, G. A. et al. Common and disorder-specific neural responses to emotional faces in generalised anxiety, social anxiety and panic disorders. Br. J. Psychiatry 206, 206–215 (2015).
Gross, C. T. & Canteras, N. S. The many paths to fear. Nat. Rev. Neurosci. 13, 651–658 (2012). Overviews the major brain circuits involved in the mediation of fear and threat behaviours in rodents; this work has been instrumental in informing current models of the dysfunctional neural systems underlying anxiety disorders.
Cryan, J. F. & Holmes, A. Model organisms: the ascent of mouse: advances in modelling human depression and anxiety. Nat. Rev. Drug Discov. 4, 775–790 (2005).
Hariri, A. R. & Holmes, A. Finding translation in stress research. Nat. Neurosci. 18, 1347–1352 (2015).
Teicher, M. H., Samson, J. A., Anderson, C. M. & Ohashi, K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat. Rev. Neurosci. 17, 652–666 (2016).
Fonzo, G. A. et al. Early life stress and the anxious brain: evidence for a neural mechanism linking childhood emotional maltreatment to anxiety in adulthood. Psychol. Med. 46, 1037–1054 (2016).
Swartz, J. R., Knodt, A. R., Radtke, S. R. & Hariri, A. R. A neural biomarker of psychological vulnerability to future life stress. Neuron 85, 505–511 (2015).
van Rooij, S. J. H. et al. Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder. Psychol. Med. 45, 2737–2746 (2015).
Yang, R. J. et al. Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning. Neuropsychopharmacology 33, 2595–2604 (2008).
Hodes, G. E., Kana, V., Menard, C., Merad, M. & Russo, S. J. Neuroimmune mechanisms of depression. Nat. Neurosci. 18, 1386–1393 (2015).
Daskalakis, N. P. et al. New translational perspectives for blood-based biomarkers of PTSD: from glucocorticoid to immune mediators of stress susceptibility. Exp. Neurol. 284, 133–140 (2016).
Zannas, A. S. & Binder, E. B. Gene–environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. Genes Brain Behav. 13, 25–37 (2014).
Roozendaal, B., McEwen, B. S. & Chattarji, S. Stress, memory and the amygdala. Nat. Rev. Neurosci. 10, 423–433 (2009).
Myers, B., McKlveen, J. M. & Herman, J. P. Glucocorticoid actions on synapses, circuits, and behavior: implications for the energetics of stress. Front. Neuroendocrinol. 35, 180–196 (2014).
Zorn, J. V. et al. Cortisol stress reactivity across psychiatric disorders: a systematic review and meta-analysis. Psychoneuroendocrinology 77, 25–36 (2017).
Kendler, K. S. Twin studies of psychiatric illness: an update. Arch. Gen. Psychiatry 58, 1005–1014 (2001).
Holmes, A. & Singewald, N. Individual differences in recovery from traumatic fear. Trends Neurosci. 36, 23–31 (2013).
Kendler, K. S. et al. The structure of genetic and environmental risk factors for syndromal and subsyndromal common DSM-IV axis I and all axis II disorders. Am. J. Psychiatry 168, 29–39 (2011).
Waszczuk, M. A., Zavos, H. M. S., Gregory, A. M. & Eley, T. C. The phenotypic and genetic structure of depression and anxiety disorder symptoms in childhood, adolescence, and young adulthood. JAMA Psychiatry 71, 905–916 (2014).
Kendler, K. S., Prescott, C. A., Myers, J. & Neale, M. C. The structure of genetic and environmental risk factors for common psychiatric and substance use disorders in men and women. Arch. Gen. Psychiatry 60, 929–937 (2003).
Weber, H. et al. Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing. Mol. Psychiatry 21, 813–822 (2016).
Howe, A. S. et al. Candidate genes in panic disorder: meta-analyses of 23 common variants in major anxiogenic pathways. Mol. Psychiatry 21, 665–679 (2016).
Smith, D. J. et al. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci. Mol. Psychiatry 21, 749–757 (2016).
Euesden, J., Lewis, C. M. & O’Reilly, P. F. PRSice: polygenic risk score software. Bioinformatics 31, 1466–1468 (2015).
Selzam, S. et al. Predicting educational achievement from DNA. Mol. Psychiatry 22, 267–272 (2017).
Arloth, J. et al. Genetic differences in the immediate transcriptome response to stress predict risk-related brain function and psychiatric disorders. Neuron 86, 1189–1202 (2015).
Gunduz-Cinar, O. et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Mol. Psychiatry 18, 813–823 (2013).
Stevens, J. S. et al. PACAP receptor gene polymorphism impacts fear responses in the amygdala and hippocampus. Proc. Natl Acad. Sci. USA 111, 3158–3163 (2014).
Fernandes, V. & Oório, F. L. Are there associations between early emotional trauma and anxiety disorders? Evidence from a systematic literature review and meta-analysis. Eur. Psychiatry 30, 756–764 (2015).
Faravelli, C. et al. The role of life events and HPA axis in anxiety disorders: a review. Curr. Pharm. Des. 18, 5663–5674 (2012).
Maren, S. & Holmes, A. Stress and fear extinction. Neuropsychopharmacology 41, 58–79 (2016).
Chattarji, S., Tomar, A., Suvrathan, A., Ghosh, S. & Rahman, M. M. Neighborhood matters: divergent patterns of stress-induced plasticity across the brain. Nat. Neurosci. 18, 1364–1375 (2015).
McEwen, B. S. et al. Mechanisms of stress in the brain. Nat. Neurosci. 18, 1353–1363 (2015).
Kendler, K. S. & Baker, J. H. Genetic influences on measures of the environment: a systematic review. Psychol. Med. 37, 615–626 (2007).
Eley, T. C., Napolitano, M., Lau, J. Y. F. & Gregory, A. M. Does childhood anxiety evoke maternal control? A genetically informed study. J. Child Psychol. Psychiatry 51, 772–779 (2010).
Eley, T. C., Gregory, A. M., Clark, D. M. & Ehlers, A. Feeling anxious: a twin study of panic/somatic ratings, anxiety sensitivity and heartbeat perception in children. J. Child Psychol. Psychiatry 48, 1184–1191 (2007).
Murray, L., Creswell, C. & Cooper, P. J. The development of anxiety disorders in childhood: an integrative review. Psychol. Med. 39, 1413–1423 (2009).
Eley, T. C. et al. The intergenerational transmission of anxiety: a children-of-twins study. Am. J. Psychiatry 172, 630–637 (2015).
Kendler, K. S., Myers, J. & Prescott, C. A. The etiology of phobias: an evaluation of the stress-diathesis model. Arch. Gen. Psychiatry 59, 242–248 (2002).
Lau, J. Y. F., Gregory, A. M., Goldwin, M. A., Pine, D. S. & Eley, T. C. Assessing gene–environment interactions on anxiety symptom subtypes across childhood and adolescence. Dev. Psychopathol. 19, 1129–1146 (2007).
Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996).
Caspi, A. et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301, 386–389 (2003).
Stein, M. B., Schork, N. J. & Gelernter, J. Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology 33, 312–319 (2008).
Holmes, A., Murphy, D. L. & Crawley, J. N. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol. Psychiatry 54, 953–959 (2003).
Homberg, J. R. & Lesch, K.-P. Looking on the bright side of serotonin transporter gene variation. Biol. Psychiatry 69, 513–519 (2011).
Sharpley, C. F., Palanisamy, S. K. A., Glyde, N. S., Dillingham, P. W. & Agnew, L. L. An update on the interaction between the serotonin transporter promoter variant (5-HTTLPR), stress and depression, plus an exploration of non-confirming findings. Behav. Brain Res. 273, 89–105 (2014).
Karg, K., Burmeister, M., Shedden, K. & Sen, S. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited. Arch. Gen. Psychiatry 68, 444–454 (2011).
Caspi, A., Hariri, A. R., Holmes, A., Uher, R. & Moffitt, T. E. Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am. J. Psychiatry 167, 509–527 (2010).
Keers, R. et al. A genome-wide test of the differential susceptibility hypothesis reveals a genetic predictor of differential response to psychological treatments for child anxiety disorders. Psychother. Psychosom. 85, 146–158 (2016).
Coleman, J. R. I. et al. Genome-wide association study of response to cognitive–behavioural therapy in children with anxiety disorders. Br. J. Psychiatry 209, 236–243 (2016).
Bale, T. L. Lifetime stress experience: transgenerational epigenetics and germ cell programming. Dialogues Clin. Neurosci. 16, 297–305 (2014).
Dias, B. G., Maddox, S. A., Klengel, T. & Ressler, K. J. Epigenetic mechanisms underlying learning and the inheritance of learned behaviors. Trends Neurosci. 38, 96–107 (2015).
Turecki, G. & Meaney, M. J. Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review. Biol. Psychiatry 79, 87–96 (2016).
Bale, T. L. & Epperson, C. N. Sex as a biological variable: who, what, when, why, and how. Neuropsychopharmacology 42, 386–396 (2017).
Cover, K. K., Maeng, L. Y., Lebrón-Milad, K. & Milad, M. R. Mechanisms of estradiol in fear circuitry: implications for sex differences in psychopathology. Transl Psychiatry 4, e422 (2014).
Lebron-Milad, K. & Milad, M. R. Sex differences, gonadal hormones and the fear extinction network: implications for anxiety disorders. Biol. Mood Anxiety Disord. 2, 3 (2012).
Maeng, L. Y. & Milad, M. R. Sex differences in anxiety disorders: interactions between fear, stress, and gonadal hormones. Horm. Behav. 76, 106–117 (2015).
Mendoza-garcés, L. et al. Differential expression of estrogen receptors in two hippocampal regions during the estrous cycle of the rat. Anat. Rec. (Hoboken) 294, 1913–1919 (2011).
Hwang, M. J. et al. Contribution of estradiol levels and hormonal contraceptives to sex differences within the fear network during fear conditioning and extinction. BMC Psychiatry 15, 295 (2015).
Zeidan, F. et al. Brain mechanisms supporting the modulation of pain by mindfulness meditation. J. Neurosci. 31, 5540–5548 (2011).
Shvil, E. et al. Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study. Neurobiol. Learn. Mem. 113, 101–108 (2014).
Glover, E. et al. Inhibition of fear is differentially associated with cycling estrogen levels in women. J. Psychiatry Neurosci. 38, 341–348 (2013).
Inslicht, S. S. et al. Sex differences in fear conditioning in posttraumatic stress disorder. J. Psychiatr. Res. 47, 64–71 (2013).
First, M. B., Williams, J. B. W., Karg, R. S. & Spitzer, R. L. Structured Clinical Interview for DSM-5® Disorders — Clinician Version (SCID-5-CV) (APA Publishing, 2016).
Sheehan, D. V. et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J. Clin. Psychiatry 59 (Suppl. 20), 22–33 (1998).
Robins, L. N. et al. The Composite International Diagnostic Interview. An epidemiologic Instrument suitable for use in conjunction with different diagnostic systems and in different cultures. Arch. Gen. Psychiatry 45, 1069–1077 (1988).
Schniering, C. A., Hudson, J. L. & Rapee, R. M. Issues in the diagnosis and assessment of anxiety disorders in children and adolescents. Clin. Psychol. Rev. 20, 453–478 (2000).
Zimmerman, M. & Galione, J. Psychiatrists’ and nonpsychiatrist physicians’ reported use of the DSM-IV criteria for major depressive disorder. J. Clin. Psychiatry 71, 235–238 (2010).
Zimmerman, M. & McGlinchey, J. B. Why don’t psychiatrists use scales to measure outcome when treating depressed patients? J. Clin. Psychiatry 69, 1916–1919 (2008).
Vermani, M., Marcus, M. & Katzman, M. A. Rates of detection of mood and anxiety disorders in primary care: a descriptive, cross-sectional study. Prim. Care Companion CNS Disord. 13, e1–e10 (2011).
First, M. B. et al. How do clinicians actually use the diagnostic and statistical manual of mental disorders in clinical practice and why we need to know more. J. Nerv. Ment. Dis. 202, 841–844 (2014).
Kessler, R. C. et al. Past-year use of outpatient services for psychiatric problems in the National Comorbidity Survey. Am. J. Psychiatry 156, 115–123 (1999).
Roy-Byrne, P. P. et al. Anxiety disorders and comorbid medical illness. Gen. Hosp. Psychiatry 30, 208–225 (2008).
Craske, M. G. & Stein, M. B. Anxiety. Lancet 388, 3048–3059 (2016).
Bandelow, B. et al. Biological markers for anxiety disorders, OCD and PTSD — a consensus statement. Part I: neuroimaging and genetics. World J. Biol. Psychiatry 17, 321–365 (2016).
Spitzer, R. L., Kroenke, K., Williams, J. B. W. & Löwe, B. A brief measure for assessing generalized anxiety disorder. Arch. Intern. Med. 166, 1092–1097 (2006).
Plummer, F., Manea, L., Trepel, D. & McMillan, D. Screening for anxiety disorders with the GAD-7 and GAD-2: a systematic review and diagnostic metaanalysis. Gen. Hosp. Psychiatry 39, 24–31 (2016).
Zigmond, A. S. & Snaith, R. P. The hospital anxiety and depression scale. Acta Psychiatr. Scand. 67, 361–370 (1983).
Campbell-Sills, L. et al. Validation of a brief measure of anxiety-related severity and impairment: the Overall Anxiety Severity and Impairment Scale (OASIS). J. Affect. Disord. 112, 92–101 (2009).
Birmaher, B. et al. The Screen for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psychometric characteristics. J. Am. Acad. Child Adolesc. Psychiatry 36, 545–553 (1997).
Muris, P., Merckelbach, H., Schmidt, H. & Mayer, B. The revised version of the Screen for Child Anxiety Related Emotional Disorders (SCARED-R): factor structure in normal children. Pers. Individ. Dif. 26, 99–112 (1998).
Spence, S. H. A measure of anxiety symptoms among children. Behav. Res. Ther. 36, 545–566 (1998).
Nauta, M. H. et al. A parent-report measure of children's anxiety: psychometric properties and comparison with child-report in a clinic and normal sample. Behav. Res. Ther. 42, 813–839 (2004).
Edwards, S. L., Rapee, R. M., Kennedy, S. J. & Spence, S. H. The assessment of anxiety symptoms in preschool-aged children: the revised Preschool Anxiety Scale. J. Clin. Child Adolesc. Psychol. 39, 400–409 (2010).
Lyneham, H. J., Rapee, R. M. & Hudson, J. L. in The Wiley Handbook of Anxiety Disorders (eds Emmelkamp, P. & Ehring, T. ) 623–642 (John Wiley & Sons, 2014).
García-Campayo, J. et al. Primary prevention of anxiety disorders in primary care: a systematic review. Prev. Med. 76, S12–S15 (2015).
Higgins, E. & O'sullivan, S. ‘What Works’: systematic review of the ‘FRIENDS for Life’ programme as a universal school-based intervention programme for the prevention of child and youth anxiety. Educ. Psychol. Pract. 31, 424–438 (2015).
Fisak, B. J., Richard, D. & Mann, A. The prevention of child and adolescent anxiety: a meta-analytic review. Prev. Sci. 12, 255–268 (2011).
Teubert, D. & Pinquart, M. A meta-analytic review on the prevention of symptoms of anxiety in children and adolescents. J. Anxiety Disord. 25, 1046–1059 (2011).
Ginsburg, G. S., Drake, K. L., Tein, J.-Y., Teetsel, R. & Riddle, M. A. Preventing onset of anxiety disorders in offspring of anxious parents: a randomized controlled trial of a family-based intervention. Am. J. Psychiatry 172, 1207–1214 (2015).
Gardenswartz, C. A. & Craske, M. G. Prevention of panic disorder. Behav. Ther. 32, 725–737 (2001).
Rapee, R. M., Lau, E. X. & Kennedy, S. J. The Cool Little Kids Anxiety Prevention Program — Therapist Manual (Centre for Emotional Health, 2010).
Rapee, R. M., Kennedy, S. J., Ingram, M., Edwards, S. L. & Sweeney, L. Altering the trajectory of anxiety in at-risk young children. Am. J. Psychiatry 167, 1518–1525 (2010).
Rapee, R. M. The preventative effects of a brief, early intervention for preschool-aged children at risk for internalising: follow-up into middle adolescence. J. Child Psychol. Psychiatry 54, 780–788 (2013). Describes some of the longest outcomes in the mental health prevention literature; for example, early interventions in individuals with anxious temperament can have powerful long-term benefits.
Wang, P. S. et al. Delay and failure in treatment seeking after first onset of mental disorders in the World Health Organization's World Mental Health Survey Initiative. World Psychiatry 6, 177–185 (2007).
National Institute for Health and Care Excellence. Anxiety disorders: guidance and guidelines. NICEhttps://www.nice.org.uk/guidance/qs53 (2014).
Katzman, M. A. et al. Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive–compulsive disorders. BMC Psychiatry 14, S1 (2014).
Bandelow, B., Lichte, T., Rudolf, S., Wiltink, J. & Beutel, M. E. The German guidelines for the treatment of anxiety disorders. Eur. Arch. Psychiatry Clin. Neurosci. 265, 363–373 (2015).
Lim, L. et al. Ministry of Health clinical practice guidelines: anxiety disorders. Singapore Med. J. 56, 310–315 (2015).
McHugh, R. K., Whitton, S. W., Peckham, A. D., Welge, J. A. & Otto, M. W. Patient preference for psychological versus pharmacologic treatment of psychiatric disorders. J. Clin. Psychiatry 74, 595–602 (2013).
Manassis, K. et al. Types of parental involvement in CBT with anxious youth: a preliminary meta-analysis. J. Consult. Clin. Psychol. 82, 1163–1172 (2014). This meta-analysis provides a strong and unique perspective on a controversial issue: whether treatments for child anxiety benefit from the inclusion of parents.
James, A. C., James, G., Cowdrey, F. A., Soler, A. & Choke, A. Cognitive behavioural therapy for anxiety disorders in children and adolescents. Cochrane Database Syst. Rev. 3, CD004690 (2013).
Hofmann, S. G. & Smits, J. A. J. Cognitive–behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. J. Clin. Psychiatry 69, 621–632 (2008).
Cuijpers, P., Cristea, I. A., Karyotaki, E., Reijnders, M. & Huibers, M. J. H. How effective are cognitive behavior therapies for major depression and anxiety disorders? A meta-analytic update of the evidence. World Psychiatry 15, 245–258 (2016). This meta-analysis presents a large body of evidence demonstrating the efficacy of CBT for social anxiety disorder, panic disorder and generalized anxiety disorder.
Emmrich, A. et al. Depression does not affect the treatment outcome of CBT for panic and agoraphobia: results from a multicenter randomized trial. Psychother. Psychosom. 81, 161–172 (2012).
Hofmann, S. G., Wu, J. Q. & Boettcher, H. Effect of cognitive–behavioral therapy for anxiety disorders on quality of life: a meta-analysis. J. Consult. Clin. Psychol. 82, 375–391 (2014).
Loerinc, A. G. et al. Response rates for CBT for anxiety disorders: need for standardized criteria. Clin. Psychol. Rev. 42, 72–82 (2015).
Ishikawa, S., Okajima, I., Matsuoka, H. & Sakano, Y. Cognitive behavioural therapy for anxiety disorders in children and adolescents: a meta-analysis. Child Adolesc. Ment. Health 12, 164–172 (2007).
Vøllestad, J., Nielsen, M. B. & Nielsen, G. H. Mindfulness- and acceptance-based interventions for anxiety disorders: a systematic review and meta-analysis. Br. J. Clin. Psychol. 51, 239–260 (2012).
Keefe, J. R., McCarthy, K. S., Dinger, U., Zilcha-Mano, S. & Barber, J. P. A meta-analytic review of psychodynamic therapies for anxiety disorders. Clin. Psychol. Rev. 34, 309–323 (2014).
Cuijpers, P., Donker, T., Weissman, M. M., Ravitz, P. & Cristea, I. A. Interpersonal psychotherapy for mental health problems: a comprehensive meta-analysis. Am. J. Psychiatry 173, 680–687 (2016).
Vos, S. P. F., Huibers, M. J. H., Diels, L. & Arntz, A. A randomized clinical trial of cognitive behavioral therapy and interpersonal psychotherapy for panic disorder with agoraphobia. Psychol. Med. 42, 2661–2672 (2012).
Higa-McMillan, C. K., Francis, S. E., Rith-Najarian, L. & Chorpita, B. F. Evidence base update: 50 years of research on treatment for child and adolescent anxiety. J. Clin. Child Adolesc. Psychol. 45, 91–113 (2016). This review provides a thorough and systematic evaluation of the key active components in treatments for anxious youths.
Griebel, G. & Holmes, A. 50 years of hurdles and hope in anxiolytic drug discovery. Nat. Rev. Drug Discov. 12, 667–687 (2013).
Murrough, J. W., Yaqubi, S., Sayed, S. & Charney, D. S. Emerging drugs for the treatment of anxiety. Expert Opin. Emerg. Drugs 20, 393–406 (2015).
Ravindran, L. N. & Stein, M. B. The pharmacologic treatment of anxiety disorders. J. Clin. Psychiatry 71, 839–854 (2010). A review paper focusing on advances in pharmacotherapy for anxiety disorders up to 2010.
Sadock, B. J., Kaplan, H. I., Sadock, V. A. & Ruiz, P. Kaplan and Sadock's Comprehensive Textbook of Psychiatry 10th edn Vol. 1 (Lippincott Williams & Wilkins, 2017, forthcoming).
Gommoll, C. et al. A double-blind, randomized, placebo-controlled, fixed-dose phase III study of vilazodone in patients with generalized anxiety disorder. Depress. Anxiety 32, 451–459 (2015).
Stein, D. J. et al. Agomelatine in generalized anxiety disorder. J. Clin. Psychiatry 75, 362–368 (2014).
Baldwin, D. S. et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J. Psychopharmacol. 28, 403–439 (2014). Guidelines from the British Association for Psychopharmacology on pharmacological treatment options for anxiety disorders.
Gray, S. L. Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study. BMJ. 352, i90 (2016).
Kreys, T.-J. M. & Phan, S. V. A. Literature review of quetiapine for generalized anxiety disorder. Pharmacother. J. Hum. Pharmacol. Drug Ther. 35, 175–188 (2015).
Steenen, S. A. et al. Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. J. Psychopharmacol. 30, 128–139 (2016).
Mohatt, J., Bennett, S. M. & Walkup, J. T. Treatment of separation, generalized, and social anxiety disorders in youths. Am. J. Psychiatry 171, 741–748 (2014).
Wehry, A. M., Beesdo-Baum, K., Hennelly, M. M., Connolly, S. D. & Strawn, J. R. Assessment and treatment of anxiety disorders in children and adolescents. Curr. Psychiatry Rep. 17, 52 (2015).
Bridge, J. A. et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment. JAMA 297, 1683–1696 (2007).
Marchesi, C. et al. Clinical management of perinatal anxiety disorders: a systematic review. J. Affect. Disord. 190, 543–550 (2016).
Cuijpers, P. et al. The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. World Psychiatry 12, 137–148 (2013).
Cuijpers, P. et al. Adding psychotherapy to antidepressant medication in depression and anxiety disorders: a meta-analysis. World Psychiatry 13, 56–67 (2014).
Piacentini, J. et al. 24- and 36-week outcomes for the Child/Adolescent Anxiety Multimodal Study (CAMS). J. Am. Acad. Child Adolesc. Psychiatry 53, 297–310 (2014).
Ginsburg, G. S. et al. Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry 71, 310–318 (2014).
Heldt, E. et al. Predictors of relapse in the second follow-up year post cognitive–behavior therapy for panic disorder. Rev. Bras. Psiquiatr. 33, 23–29 (2011).
van Apeldoorn, F. J. et al. A randomized trial of cognitive-behavioral therapy or selective serotonin reuptake inhibitor or both combined for panic disorder with or without agoraphobia. J. Clin. Psychiatry 71, 574–586 (2010).
White, K. S. et al. Does maintenance CBT contribute to long-term treatment response of panic disorder with or without agoraphobia? A randomized controlled clinical trial. J. Consult. Clin. Psychol. 81, 47–57 (2013).
Craske, M. G. et al. CBT intensity and outcome for panic disorder in a primary care setting. Behav. Ther. 37, 112–119 (2006).
Scholten, W. D., Batelaan, N. M., van Oppen, P., Smit, J. H. & van Balkom, A. J. L. M. Discontinuation of antidepressants in remitted anxiety disorder patients: the need for strategies to prevent relapse. Psychother. Psychosom. 82, 399–400 (2013).
Donovan, M. R., Glue, P., Kolluri, S. & Emir, B. Comparative efficacy of antidepressants in preventing relapse in anxiety disorders — a meta-analysis. J. Affect. Disord. 123, 9–16 (2010).
Perna, G., Alciati, A., Riva, A., Micieli, W. & Caldirola, D. Long-term pharmacological treatments of anxiety disorders: an updated systematic review. Curr. Psychiatry Rep. 18, 23 (2016).
Schneider, R. L., Arch, J. J. & Wolitzky-Taylor, K. B. The state of personalized treatment for anxiety disorders: a systematic review of treatment moderators. Clin. Psychol. Rev. 38, 39–54 (2015).
Hudson, J. L. et al. Clinical predictors of response to cognitive–behavioral therapy in pediatric anxiety disorders: the Genes for Treatment (GxT) Study. J. Am. Acad. Child Adolesc. Psychiatry 54, 454–463 (2015).
Bittner, A. et al. What characteristics of primary anxiety disorders predict subsequent major depressive disorder? J. Clin. Psychiatry 65, 618–626 (2004).
Castaneda, A. E., Tuulio-Henriksson, A., Marttunen, M., Suvisaari, J. & Lönnqvist, J. A review on cognitive impairments in depressive and anxiety disorders with a focus on young adults. J. Affect. Disord. 106, 1–27 (2008).
Eysenck, M. W., Derakshan, N., Santos, R. & Calvo, M. G. Anxiety and cognitive performance: attentional control theory. Emotion 7, 336–353 (2007).
Kessler, R. C. et al. The global burden of mental disorders: an update from the WHO World Mental Health (WMH) surveys. Epidemiol. Psichiatr. Soc. 18, 23–33 (2009).
Saeed Mirza, S., Ikram, M. A., Hofman, A. & Tiemeier, H. Anxiety does not predict mortality. A population-based study. World Psychiatry 14, 103–104 (2015).
Whiteford, H. A. et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 382, 1575–1586 (2013).
Hoagwood, K. & Olin, S. S. The NIMH blueprint for change report: research priorities in child and adolescent mental health. J. Am. Acad. Child Adolesc. Psychiatry 41, 760–767 (2002).
Holmes, E. A., Craske, M. G. & Graybiel, A. M. Psychological treatments: a call for mental-health science. Nature 511, 287–289 (2014).
Waters, A. M. & Craske, M. G. Towards a cognitive-learning formulation of youth anxiety: a narrative review of theory and evidence and implications for treatment. Clin. Psychol. Rev. 50, 50–66 (2016).
Bouton, M. E. Context, ambiguity, and unlearning: sources of relapse after behavioral extinction. Biol. Psychiatry 52, 976–986 (2002).
Craske, M. G., Treanor, M., Conway, C. C., Zbozinek, T. & Vervliet, B. Maximizing exposure therapy: an inhibitory learning approach. Behav. Res. Ther. 58, 10–23 (2014).
Ori, R. et al. Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorder. Cochrane Database Syst. Rev. 10, CD007803 (2015).
Kredlow, M. A., Unger, L. D. & Otto, M. W. Harnessing reconsolidation to weaken fear and appetitive memories: a meta-analysis of post-retrieval extinction effects. Psychol. Bull. 142, 314–336 (2016).
Hardwicke, T. E., Taqi, M. & Shanks, D. R. Postretrieval new learning does not reliably induce human memory updating via reconsolidation. Proc. Natl Acad. Sci. USA 113, 5206–5211 (2016).
Christensen, H., Batterham, P. & Calear, A. Online interventions for anxiety disorders. Curr. Opin. Psychiatry 27, 7–13 (2014).
Olthuis, J. V., Watt, M. C., Bailey, K., Hayden, J. A. & Stewart, S. H. Therapist-supported Internet cognitive behavioural therapy for anxiety disorders in adults. Cochrane Database Syst. Rev. 12, CD011565 (2016). This Cochrane review summarizes the evidence supporting the use of Internet-based CBTs for anxiety disorders.
Ye, X. et al. Effectiveness of Internet-based interventions for children, youth, and young adults with anxiety and/or depression: a systematic review and meta-analysis. BMC Health Serv. Res. 14, 313 (2014).
Pennant, M. E. et al. Computerised therapies for anxiety and depression in children and young people: a systematic review and meta-analysis. Behav. Res. Ther. 67, 1–18 (2015).
Cristea, I. A., Kok, R. N. & Cuijpers, P. Efficacy of cognitive bias modification interventions in anxiety and depression: meta-analysis. Br. J. Psychiatry 206, 7–16 (2015).
Heeren, A., Mogoase, C., Philippot, P. & McNally, R. J. Attention bias modification for social anxiety: a systematic review and meta-analysis. Clin. Psychol. Rev. 40, 76–90 (2015).
van Ginneken, N. et al. Non-specialist health worker interventions for the care of mental, neurological and substance-abuse disorders in low- and middle-income countries. Cochrane Database Syst. Rev. 19, CD009149 (2013). This Cochrane review presents evidence for mental health treatments, including treatments for anxiety, delivered by non-specialists in low-to-middle-income countries.
Kobak, K. A., Craske, M. G., Rose, R. D. & Wolitsky-Taylor, K. Web-based therapist training on cognitive behavior therapy for anxiety disorders: a pilot study. Psychotherapy 50, 235–247 (2013).
Craske, M. G. et al. Disorder-specific impact of coordinated anxiety learning and management treatment for anxiety disorders in primary care. Arch. Gen. Psychiatry 68, 378–388 (2011).
Gilmartin, M. R., Balderston, N. L. & Helmstetter, F. J. Prefrontal cortical regulation of fear learning. Trends Neurosci. 37, 455–464 (2014).
Dunsmoor, J. E. & Paz, R. Fear generalization and anxiety: behavioral and neural mechanisms. Biol. Psychiatry 78, 336–343 (2015).
Singewald, N., Schmuckermair, C., Whittle, N., Holmes, A. & Ressler, K. J. Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders. Pharmacol. Ther. 149, 150–190 (2015).
Insel, T. et al. Research Domain Criteria (RDoC): toward a new classification framework for research on mental disorders. Am. J. Psychiatry 167, 748–751 (2010).
Sanislow, C. A. et al. Developing constructs for psychopathology research: research domain criteria. J. Abnorm. Psychol. 119, 631–639 (2010).
Wittchen, H.-U. et al. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J. Clin. Psychiatry 63 (Suppl. 8), 24–34 (2002).
van de Water, T., Suliman, S. & Seedat, S. Gender and cultural issues in psychiatric nosological classification systems. CNS Spectr. 21, 334–340 (2016).
Craske, M. G. Cognitive–Behavioral Therapy (American Psychological Association, 2010).
Milad, M. R. & Quirk, G. J. Fear extinction as a model for translational neuroscience: ten years of progress. Annu. Rev. Psychol. 63, 129–151 (2012).
McNaughton, N. The conceptual nervous system of J.A. Gray: anxiety and neuroticism. Neurosci. Biobehav. Rev. 28, 227–228 (2004).
Harris, A. Z. & Gordon, J. A. Long-range neural synchrony in behavior. Annu. Rev. Neurosci. 38, 171–194 (2015).
Robinson, O. J. et al. Towards a mechanistic understanding of pathological anxiety: the dorsal medial prefrontal–amygdala ‘aversive amplification’ circuit in unmedicated generalized and social anxiety disorder. Lancet Psychiatry 1, 294–302 (2014).
Shin, L. M. & Liberzon, I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169–191 (2010).
Lanius, R. A., Bluhm, R., Lanius, U. & Pain, C. A review of neuroimaging studies in PTSD: heterogeneity of response to symptom provocation. J. Psychiatr. Res. 40, 709–729 (2006).
Fonzo, G. A. et al. Exaggerated and disconnected insular-amygdalar blood oxygenation level-dependent response to threat-related emotional faces in women with intimate-partner violence posttraumatic stress disorder. Biol. Psychiatry 68, 433–441 (2010).
Marin, M.-F. et al. Association of resting metabolism in the fear neural network with extinction recall activations and clinical measures in trauma-exposed individuals. Am. J. Psychiatry 173, 930–938 (2016).
Freitas-Ferrari, M. C. et al. Neuroimaging in social anxiety disorder: a systematic review of the literature. Prog. Neuropsychopharmacol. Biol. Psychiatry 34, 565–580 (2010).
Cremers, H. R. et al. Altered cortical–amygdala coupling in social anxiety disorder during the anticipation of giving a public speech. Psychol. Med. 45, 1521–1529 (2015).
Wittchen, H.-U. et al. The need for a behavioural science focus in research on mental health and mental disorders. Int. J. Methods Psychiatr. Res. 23, 28–40 (2014).
M.B.S. has received consulting fees in the past 3 years from Actelion Pharmaceuticals, Janssen, Neurocrine Biosciences, and Pfizer, and stock options from Oxeia Biopharmaceuticals and Resilience Therapeutics. M.B.S. also receives editorial honoraria from the journal Biological Psychiatry, and in his role of Co-Editor-in-Chief for UpToDate in Psychiatry. All other authors declare no competing interests.
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Craske, M., Stein, M., Eley, T. et al. Anxiety disorders. Nat Rev Dis Primers 3, 17024 (2017). https://doi.org/10.1038/nrdp.2017.24