hypothesis of anxiety disorders

The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building?

Affiliation.

• 1 Department of Psychiatry, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9070, USA.
• PMID: 21945290
• PMCID: PMC3698048
• DOI: 10.1016/j.neuropharm.2011.09.003

Hypotheses are scaffoldings erected in front of a building and then dismantled when the building is finished. They are indispensable for the workman; but you mustn't mistake the scaffolding for the building. Johann Wolfgang von Goethe. The neurogenesis hypothesis of affective disorders - in its simplest form - postulates that the generation of neurons in the postnatal hippocampal dentate gyrus is involved in the etiology and treatment efficacy of major depressive disorder (MDD). The hypothesis was established in the 1990s but was built on a broad foundation of earlier research on the hippocampus, serotonin and MDD. It has gone through several growth phases fueled by discoveries both correlative and causative in nature. Recently, the hypothesis has also been broadened to also include potential relevance for anxiety disorders, like post-traumatic stress disorder (PTSD). As any hypothesis should be, it has been tested and challenged, sometimes vigorously. Here we review the current standing of the neurogenesis hypothesis of affective and anxiety disorders, noting in particular how a central postulate - that decreased neurogenesis results in depression or anxiety - has, in general, been rejected. We also review the controversies on whether treatments for these disorders, like antidepressants, rely on intact neurogenesis for their efficacy, and the existence of neurogenesis-dependent and -independent effects of antidepressants. In addition, we review the implications that the hypothesis has for the response to stress, PTSD, and the neurobiology of resilience, and highlight our own work showing that adult-generated neurons are functionally important for the behavioral response to social stress. We conclude by emphasizing how advancements in transgenic mouse technology, rodent behavioral analyses, and our understanding of the neurogenesis process will allow us to refine our conclusions and perform ever more specific experiments. Such scrutiny is critical, since if we "mistake the scaffolding for the building" we could overlook opportunities for translational impact in the clinic. This article is part of a special Issue entitled 'Anxiety and Depression'.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't
• Research Support, U.S. Gov't, Non-P.H.S.
• Anti-Anxiety Agents / pharmacology
• Anti-Anxiety Agents / therapeutic use
• Anxiety / drug therapy
• Anxiety / genetics
• Anxiety / pathology
• Hippocampus / drug effects
• Hippocampus / pathology
• Hippocampus / physiology*
• Models, Biological*
• Mood Disorders / drug therapy
• Mood Disorders / genetics
• Mood Disorders / pathology
• Neurogenesis / drug effects
• Neurogenesis / physiology*
• Anti-Anxiety Agents

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• R01 DA016765/DA/NIDA NIH HHS/United States
• CAPMC/ CIHR/Canada

Applications for the Beck Institute Certified Master Clinician program are open! Learn more .

• Aaron T. Beck

Cognitive Therapy of Anxiety Disorders: Science and Practice

Cognitive Therapy of Anxiety Disorders: Science and Practice (Clark & Beck, 2010, from Guilford Press, pp. 628) represents the outgrowth of my 26 year journey of inquiry, discovery and acquired knowledge on the cognitive basis of the emotional disorders.  It has been an honor and privilege to collaborate with Aaron T. Beck on many different projects over the years.  He has been the mentor who contributed enormously to what I know about psychological problems like anxiety and depression, and who taught me most about the importance of adopting an integrative, scientific perspective in which theory, research and practice are mutually informed by each other. 

There is, however, an ironic twist to Cognitive Therapy of Anxiety Disorders .  My introduction to Dr. Beck occurred in 1983 while I was a doctoral student at the Institute of Psychiatry, London, England.  I gave my first conference paper at the annual meeting of the British Association of Behavioural and Cognitive Psychotherapy in Hull, England.  It was on the two hour train ride escorting Dr. Beck back to London that I had my first private conversation with the founder of cognitive therapy.  Coincidentally during that train ride Dr. Beck spent much of his time writing in a notebook on what later turned out to be an innovative extension of cognitive therapy to the anxiety disorders.  This work subsequently appeared in Anxiety Disorders and Phobias: A Cognitive Perspective (Beck & Emery, 1985; Basic Books).  Never in my wildest dreams could I have imagined that 26 years later we would collaborate on a major refinement and reformulation of the very work that was taking shape as we whizzed through the English countryside so many years ago.

Cognitive Therapy of Anxiety Disorders is the result of four years of a painstaking review, evaluation and synthesis of the enormous research and clinical literature on the cognitive basis of anxiety.  There has been a paradigmatic shift in how we understand and treat the anxiety disorders since the original formulation of the cognitive model in 1985.  We felt it was timely to update and refine Beck’s cognitive model in light of substantial advances that have been made on the cognitive basis of anxiety over the last two decades.  Thus the first four chapters lay out a reformulated cognitive model of anxiety and critically review empirical support for 12 key hypotheses of the model.  Hundreds of research studies are included in this review and future directions for cognitive research are identified.

Consistent with past major publications on cognitive therapy, Cognitive Therapy of Anxiety Disorders presents the treatment as a theory-driven, empirically based system of psychotherapy.  Consequently the second part of the book provides a detailed explanation of cognitive assessment, case formulation, and intervention strategies that are based on the reformulated cognitive model outlined in the first part of the book.  A step-by-step description of the cognitive approach is provided along with dozens of clinical resources such as rating scales, checklists, structured diaries, etc.  Our intention was to provide a thorough, systematic, and practical description of cognitive assessment, formulation and treatment strategies for anxiety that could be utilized by even a novice to cognitive therapy.

The final five chapters are really mini treatment manuals for the five most prominent anxiety disorders; panic disorder, social phobia, GAD, OCD, and PTSD.  Each chapter focuses on a specific disorder and begins with a brief review of diagnostic features and phenomenological research.  This is followed by presentation of a disorder-specific application of the reformulated cognitive model to each disorder as well as a review of the key hypotheses derived from this model.  The second half of each chapter presents a step-by-step explanation of a disorder-specific cognitive assessment and treatment protocol for the anxiety disorder discussed in that chapter.  Each chapter ends with a brief review of the efficacy of cognitive therapy and suggestions for future directions.

The enormous advances made in the last 26 years on the cognitive basis of anxiety are the result of many brilliant and talented researchers from around the world.  Cognitive Therapy of Anxiety Disorders is our attempt to provide a comprehensive, in-depth evaluation, synthesis and integration of this work from the vantage point of Beck’s original insights into the problem of anxiety.  It is hoped that this publication will provide a framework for future theory and research on anxiety as well as providing practitioners with the latest clinical tools that will enhance cognitive treatment of anxiety disorders.

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• Review Article
• Published: 01 July 2004

The developmental origins of anxiety

• Cornelius Gross 1 &
• Rene Hen 2  

Nature Reviews Neuroscience volume  5 ,  pages 545–552 ( 2004 ) Cite this article

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Anxiety is a mental state that is a normal reaction to potential threat. Excessive or inappropriate anxiety can become an illness. Early developmental mechanisms are thought to contribute to the susceptibility of the adult to anxiety. Developmental mechanisms under both genetic and environmental control set the tendency of an organism to express anxiety in certain situations.

Drugs such as benzodiazepines and selective serotonin re-uptake inhibitors (SSRIs) have been used to treat excessive anxiety. These drugs target GABA A (γ-aminobutyric acid, type A) receptors and block the re-uptake of serotonin, respectively.

A small number of genetic variations have been linked to increased anxiety in humans. Studies have shown a small, but significant, increase in anxiety in both infants and adults that carry a variant of the serotonin transporter ( 5-HTT ) gene, indicating that 5-HTT influences anxiety-related behaviour.

Twin studies indicate that reduced hippocampal volume increases susceptibility to environmental stresses that presage the onset of anxiety-related behaviours such as post-traumatic stress disorder. Whether reductions of hippocampal volume have genetic or environmental origins is not yet known.

The MAOA gene has been implicated in the mechanism by which early-life trauma influences subsequent psychopathology. In boys that have been maltreated, carrying the low-activity allele of the MAOA gene increases the probability that they will develop antisocial behaviour as an adult. However, maltreated boys with the high-activity allele are not at increased risk of behaving in an antisocial manner at maturity.

Studies of genetically modified mice have made it possible to investigate the consequences on anxiety-related behaviour of manipulating specific genes. Anxiety-related behaviour is altered in mice bearing mutations in specific genes, including 5-HT 1A .

In summary, lifelong susceptibility to anxiety can be determined by the combined influence of genetic and environmental factors on early development.

Anxiety is a mental state that is elicited in anticipation of threat or potential threat. Sensations of anxiety are a normal part of human experience, but excessive or inappropriate anxiety can become an illness. In this review, we consider the evidence for anxiety as a product of early environmental experiences, the impacts of which are modulated by genetic susceptibility factors. We propose that such interactions can induce persistent structural and functional changes in the brain that underlie susceptibility to anxiety. Investigation of the molecular nature of these factors and the plastic changes that they induce has the potential to reveal why different individuals experience different levels of anxiety.

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Acknowledgements

We thank D. Leonardo, J. Gordon, A. Dranovsky, M. Rogan, K. Klemenhagen, J. Monckton, L. Santarelli and V. Carola for helpful comments and discussions.

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A psychological disorder in which the person is burdened by recurrent, persistent thoughts or ideas, and/or feels compelled to carry out a repetitive, ritualized behaviour. Anxiety is increased by attempts to resist the compulsion and is relieved by giving way to it.

A small almond-shaped structure, comprising 13 nuclei, buried in the anterior medial section of each temporal lobe.

Twins that develop from a single fertilized egg cell through its division into two genetically identical parts.

Twins that develop during the same pregnancy as the result of two separate eggs being fertilized by two separate sperm.

One of five domains of the NEO-Personality Inventory psychological assessment tool. Neuroticism comprises six facets: anxiety, depression, angry hostility, self-consciousness, impulsivity and vulnerability.

One of five domains of the NEO-Personality Inventory psychological assessment tool. Agreeableness comprises six facets: trust, straightforwardness, altruism, compliance, modesty and tender-mindedness.

Variation in DNA sequence between individuals.

Hormones produced by the adrenal cortex, which are involved in carbohydrate and protein metabolism, but also affect brain function. Cortisol (human) and corticosterone (rodent) are examples.

A chemical modification of a molecule involving the covalent attachment of a CH 3 group. Methylation of the DNA encoding a gene can alter its expression.

In the mature primary visual cortex of mammals, most neurons respond predominantly to visual inputs from one eye or the other. Cells that respond to a given eye are arranged in stripes — the ocular dominance columns — that alternate with stripes of neurons that respond to the other eye.

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REVIEW article

Biological and cognitive theories explaining panic disorder: a narrative review.

• 1 Faculty of Arts, Health and Design, Swinburne University, Hawthorn, VIC, Australia
• 2 College of Education, Psychology and Social Work, Órama Institute for Mental Health and Wellbeing, Flinders University, Bedford Park, SA, Australia

The current narrative review summarizes and examines several theories of panic disorder (PD) including biological theories, encompassing neurochemical factors, metabolic and genetic theories, respiratory and hyperventilation theories and cognitive theory. Biological theories have informed the development of psychopharmacological treatments; however, they may be limited in their utility given the efficacy of psychological treatments. In particular, behavioral and, more recently, cognitive models have garnered support due to the efficacy of cognitive-behavior therapy (CBT) in treating PD. The role of combination treatments has been found to be superior in the treatment of PD in particular cases, lending support for the need for an integrated approach and model for PD given that the etiology of PD is complex and multifactorial.

Introduction

Panic disorder (PD) is an anxiety disorder characterized by spontaneous and recurrent panic attacks (PAs) which is severe and persistent, as specified by The Diagnostic and Statistical Manual of Mental Disorders 5th ed. (DSM-5) ( 1 ). PAs are characterized by multiple physical symptoms including a pounding or racing heart, sweating, dyspnea, weakness or dizziness, feeling hot or cold chills, tingling or numbness in the hands, chest pain, or stomach pain ( 1 ). PD has often been treated by either psychopharmacological interventions and cognitive behavioral therapy (CBT) or a combination ( 2 ).

This paper reviews theories describing the etiology of PD which have relevance for our understanding of this common debilitating disorder and its treatment. The last review on theories explaining panic disorder was published over 10 years ago ( 3 ) and, while effective treatments for PD exist ( 4 ), there remains room for improvement ( 5 ) in outcomes. This paper undertakes a narrative review examining and summarizing the major approaches to understanding PD and frameworks for its treatment. Biological theories of PD have been proposed, encompassing neurochemical factors, metabolic and genetic theories, respiratory and hyperventilation theories. Furthermore, five major psychological theories have been described as bases for understanding the etiology of PD, including conditioning and related behavioral theories, cognitive theories, anxiety sensitivity theory, and psychodynamic theories. Of these, due to their current widespread use clinically, this paper focuses on cognitive and cognitive-behavioral theories of PD ( 6 , 7 ).

Despite both biological and psychological frameworks offering treatment avenues for PD, to date, they remain largely unintegrated ( 8 ). There is as yet little agreement of how best to integrate both models nor how each of the frameworks could evolve treatment approaches by integrating emerging research trends. Such integrative activity gives the potential to develop new, combined or augmented treatments.

Biological theories

Neurochemical theory.

A neurochemical imbalance of neurotransmitters in the brain, such as serotonin, norepinephrine, dopamine, and gamma-aminobutyric acid (GABA), is thought to cause PD symptoms ( 9 ). This biological theory is evidenced by the symptom reduction effects of antidepressant or anxiolytic medication in many PD suffers ( 10 ). Treatments of PD have utilized several groups of drugs including; benzodiazepines, tricyclic and heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs) ( 11 ). Nowadays, antidepressants used for aminergic symptoms are more commonly used to treat panic symptoms rather than ones that target the principal inhibitory neurotransmitters in the central nervous system (CNS) such as benzodiazepines that work on the GABA receptors ( 12 ). However, it is widely accepted that despite their effectiveness, medications that target the GABA receptors come with a high risk of addiction and impact on cognitive functioning ( 13 ).

Neurochemical theories further propose dysregulated functioning of neurochemicals leading to a deficiency in the serotonergic system or excess serotonin, in an attempt to explain the etiology of PD ( 14 ). Additionally, abnormal chemoreceptor reactivity may be involved in the etiology of PD. Amongst some of the inhibitory and excitatory neurotransmitters that may play a role in the upregulation or downregulation of panic may include glutamate, GABA, cholecystokinin, adenosine, dopamine, and norepinephrine ( 15 ). The inhibitory/excitatory framework has also been influential in recent behavioral approaches to treatment ( 16 ), and will be discussed in a following section.

Other neurochemical theories have suggested the significant involvement of the neuropeptide Y (NPY), given its a dense concentration in anxiety circuits, which has been thought to be involved in the consolidation of fear memories ( 17 ). Evidence suggests that NPY contains anxiolytic properties and serves the role as a protective neurochemical that facilitates stress resilience ( 18 ). NPY is saturated in the central nervous system, particularly in the cortical, limbic, and hypothalamic (i.e., basal ganglia, hippocampus, hypothalamus, amygdala, nucleus accumbens, cortex, periaqueductal gray, and lower brainstem) brain region ( 19 ) where located and plays a vital role in energy homeostasis, pain, control of food intake and physiological processes related to stress/stress resilience ( 20 ). Patients with anxiety disorders have showed reduced concentrations of NPY, therefore, they experience elevated risk to stress and fear responses.

Neuroanatomical theories and animal models

An association of brain regions being controlled by an anxiety network have been described by numerous researchers who have examined fear circuits in the brain ( 21 – 23 ). The thalamus is a relay station for sensory input and receives information from all senses, and analyses bodily inputs that are threatening ( 24 ). The thalamus then initiates two strategies; one is a fast and general emergency response whilst the other one is a slower, detailed analysis of the feared situation.

In the initial emergency response, the thalamus analyses the situation to determine whether the presenting threat corresponds to an innate instinctual fear. It does this by comparing the fear situation with primitive fears that are uniquely stored in an inborn survival memory ( 17 ). In an effort to maximize chances for survival in a life-threatening situation, the amygdala is alerted and a number of responses are initiated, including the activation of the sympathetic nervous system and the HPA axis.

In the slow response, the hippocampus, which is associated with learning and memory analyses the threatening situation by retrieving detailed information from all available memory sources; this includes gathered information over the years including theoretical knowledge, factual information and the recall of past unpleasant experiences. This ability assists the hippocampus to develop context and assess the situation more realistically. The amygdala is then informed that the threatening situation is not dangerous, down regulating the fear response, and consequently scaling down the physiological response.

In recent years, animal studies and brain imagery techniques have been used extensively to identify brain regions which are specifically implicated in the regulation of panic and anxiety. The limbic area, particularly the amygdala has been directly associated with the fight/flight response ( 25 ). Moreover the locus ceruleus (LC) appears to be implicated in the sleep-wake cycle, arousal, anxiety, and fear which were commonly identified brain regions relating to PD ( 26 , 27 ).

Neuroimaging studies have also highlighted the characteristic of hypoactivation in the prefrontal cortex (PFC) is observed in anxiety disorders that involve intense fear such as panic, social anxiety disorder, and post-traumatic stress disorder (PTSD), which in turn decreases the amygdala inhibition ( 28 ). In contrast, anxiety disorders that involve rumination and obsessiveness such as Generalized Anxiety Disorder (GAD) and Obsessive Compulsive Disorder (OCD) are characterized by overactivity in the PFC ( 28 ). Another neuroanatomical area thought to be involved in PD is the dorsal raphe nucleus (DRN). The DRN subdivisions comprise distinct populations of neurons that vary in their morphological nature, neurochemically and functionally. It has been found that anxiety and panic activate different subset of neurons in the DRN ( 29 – 31 ).

A study conducted by Johnson and colleagues found that exposing rats to high concentrations of hypercarbic gas substantially increased anxiety and elicited components of an adaptive panic/defense –related response as observed by increases in autonomic arousal ( 32 – 34 ). Disrupted GABA inhibition in the dorsomedial hypothalamic perifornical region (DMH/Pef) resulted in rats being susceptible to the induction of PAs following sodium lactate infusions ( 35 ). The researchers speculated that the DMH/Pef regions mediate the respiratory and autonomic, behavioral and endocrine components of the panic like response, which includes elevated heart and respiration rate, increased blood pressure, plasma catecholamine, intestinal and colonic mobility. Moreover, on the basis of animal research, there has been increased interest in the use of augmenting agents such as d-cycloserine to enhance response to cognitive-behavior therapy and, especially, exposure therapy for PD. However, despite initial augmentation of efficacy, longer-term impacts have been less successful ( 36 ). While multiple treatment studies have examined the effectiveness of pharmacological agents, few studies have focussed on neuromodulatory treatments for PD. A relatively recent review found only one of two randomized trials demonstrating efficacy of transcranial magnetic stimulation (TMS) for PD ( 37 ). A previous Cochrane Review had also concluded that there was insufficient evidence supporting the use of repetitive TMS for the treatment of PD ( 38 ). There are no studies on the use of electroconvulsive therapy for a primary diagnosis of PD ( 39 ). Hence, there is still much work to be conducted in the integration of brain-based models of PD into treatment frameworks.

Hormone theory

It has also been well documented that hormones, particularly gonadal hormones, play an influential role in influencing the frequency and intensity of PAs. Spontaneous PAs affect more women than men, and rarely start before puberty or after menopause, suggesting reproductive hormones may play a significant part in the occurrence of PAs in women ( 40 ). Harvard Medical School conducted a national comorbidity survey and found the lifetime prevalence of PD in the U.S. population stands at 4.7%, overall, 6.2% comprised of women, posing more than twice as likely than men at 3.1% ( 41 ). Interestingly, women who suffer from PD displayed decreased panic symptoms during pregnancy, delivery, and lactation, although an exacerbation of panic symptoms was observed in the post lactation phase ( 40 ). These changes are believed to be characterized by increased levels of progesterone, estrogen, and oxytocin during pregnancy and lactation ( 42 ). This implies that some pregnancy hormones may act as a protective factor toward PAs, given the less frequent and intense PAs during this period despite the pregnancy and childbirth period being thought of as one with marked and heightened anxiety and common catastrophic interpretation of physiological changes ( 42 ). However, some authors question the specific clinical relevance of high hormonal levels to PD. For instance, Masdrakis and colleague concluded that, in a sample of 24 consecutive acutely-unwell, medication-free PD patients, oxytocin plasma levels were more likely relevant to the severity of their general anxiety symptoms, rather than their specific panic symptoms ( 43 ).

Metabolic theories

Metabolic theories have also been quite popular suggesting that PD sufferers are more reactive to certain anxiety-inducing substances or conditions such as injections of lactic acid, elevated CO 2 levels, caffeine, yohimbine, m-cholorophenylpiperazine, cholecystokinin (CCK), nicotine, and alcohol ( 44 ). Researchers have used numerous procedures to try to reproduce panic-like symptoms in order to fully understand the etiology of PD, suggesting further evidence for the significance of biological theories. Some of the earlier chemicals used to successfully trigger panic like symptoms included epinephrine and norepinephrine ( 45 – 47 ). Among the most common procedures used include the pharmacological agent sodium lactate ( 48 – 51 ), hyperventilation and CO 2 challenges ( 52 – 54 ).

Researchers postulated an implication of the adenosine system in explaining panic and anxiety since caffeine challenge tests have been known to induce panic like symptoms ( 55 , 56 ). Adenosine receptors (ARs) are located and dispersed in all brain areas, and are responsible for regulating the release of neurotransmitters and the action of neuromodulators which include both inhibitory and excitatory functions ( 57 ).

The modulation of anxiety in the hypothalamus, pituitary gland, especially anterior pituitary gland has also been highlighted as important areas, these areas are involved in the synthesis and release of a number of stress-related hormones ( 58 ). A breakthrough in further understanding panic was made in the 1980s, when clinical panic was distinguished from stress-like reactions and common fear based on the finding that clinical and lactate-induced panic did not activate the hypothalamus-pituitary adrenal (HPA) axis ( 59 ). The HPA axis and its activity has been extensively researched predominantly in patients suffering from psychiatric illnesses, namely depression and anxiety disorders ( 60 ). Results to date have been inconsistent, however, studies reveal that HPA axis dysregulation is common in PD patients ( 60 ).

Behavioral responses that characterize PD patients are largely due to the hypersensitivity to CO 2 in the following three brainstem areas: the peri-aqueductal gray (PAG), the raphe nuclei (RN), and LC ( 61 ). The LC is a small nucleus located in the brain stem which contains 70% of all noradrenergic neurons in the brain. When stress activates the LC, it results in increased norepinephrine release in projection sites of the LC, including the amygdala, PFC and hippocampus ( 62 ). Serotonin-producing cells in the RN have also been identified as CO 2 sensors and play a significant role in detecting CO 2 ( 63 ). These behave as pH regulators as they regulate pH homeostasis and have been proposed to form the cellular link between serotonin, chemoreception, and panic.

The PAG has also been implicated in the pathogenesis of panic. This is evidenced by awake patients who have undergone neurosurgery involving the stimulation of the PAG. These patients elicited remarkably similar symptoms to those reported by PD patients when enduring a PA ( 64 ). These findings support the notion of a continuous trait, based on one's individual sensitivity response to increasing concentrations of CO 2 ( 60 ). Panic patients are considered to have high sensitivity to rising CO 2 levels, whereas individuals suffering from congenital central hypoventilation syndrome (CCHS) and divers have low sensitivity to CO 2 levels rising ( 65 , 66 ).

Genetic theories

Amongst the most prominent biological theories are the genetic and hereditary studies that proposed individuals with PD may have inherited genetic predisposition toward the disorder. The prevalence of PD among families of PD patients is very common with evidence suggesting that amongst first-degree relatives of PD patients, there have been up to threefold increases in prevalence. Moreover, it was observed that 25% of the first-degree relatives of PD patients received a diagnosis of PD amongst first-degree relatives of PD patients ( 67 – 69 ).

Twin studies have contributed valuable information including that 31% of the monozygotic twins had a similar diagnosis compared to 0% of dizygotic twins ( 70 ). Another study showed that PAs in monozygotic twins were five times as likely to occur than in dizygotic twins PD patients. However, this study only used a small number of twins and the results may not be conclusive and may be explained by the fact that monozygotic twins share more similar environmental experiences and are commonly treated more similarly than dizygotic twins.

Other twin studies have proposed a notable hereditary correlation contribution of 30–48% for PD and > 50% for agoraphobia with the pathogenesis of PD ( 71 , 72 ). Criticisms of genetic theories have included failure to yet identify a mode of inheritance in line with Mendelian patterns, thus pointing to a complex genetic inheritance model with interactions of multiple vulnerabilities and genes ( 17 ). To date, only a few risk genes have been identified and even less explored is the gene-environment interactions specific to PD. Moreover, treatment or intervention implications have yet to evolve but approaches to individualized medicine are beginning to discuss the potential role of pharmacogenetics.

Recent developments in pharmacogenetics, although limited and at its infancy, appear to offer noteworthy information regarding the individuality factor or lack thereof of the response of PD associated genes toward medication ( 73 ). It is commonly argued that SSRIs is the recommended first-line psychopharmacological intervention in PD ( 74 ). Associations between PD and the serotonin system were observable through 5-HT manipulation ( 74 ), a link between SLC6A4 gene polymorphism may predispose individuals to PD ( 75 ), and an increased susceptibility for PD for 5-HT2A/5-HT1A serotonin receptor genes ( 76 ). Interestingly, certain reviews have pointed out inconsistency within the standard pharmacological treatment of different cultural population (i.e., Asian, Caucasian), which calls for a greater focus on individualized pharmacogenetics ( 73 ).

Respiratory and hyperventilation theories

Neurobiological theories namely the respiratory and hyperventilation theories attempt to explain the etiology of panic based on the notion that PAs may be caused by a dysfunctional respiratory system ( 53 , 77 – 80 ). Several theorists have proposed a causality relationship between hyperventilation and PAs, particularly characterized with an imbalance between O 2 inhaled and CO 2 exhaled during hyperventilation, thus reducing CO 2 levels in the body ( 81 ). Individuals who hyperventilate in an effort to compensate for the reduction in respiratory rate experience secondary systems, which include shortness of breath, dizziness, trembling, and palpitations ( 72 , 82 ).

The abovementioned findings led Klein to propose that the principal disturbance in PD may be explained by dysfunctional suffocation monitor (a “false suffocation alarm”, FSA), with dyspnea as the primary feature ( 42 ). The FSA asserts that high CO 2 levels typically serve as a warning marker that the individual may suffer from imminent suffocation, given that high levels of CO 2 correspond with low levels of O 2 . According to Klein, this suffocation threshold is pathologically lowered in PD patients where the FSA is argued to be hypersensitive to CO 2 compared to non-PD sufferers, with low levels of CO 2 becoming a signal for low O 2 supply. As a result, the brain's suffocation monitor is incorrectly activated based on the signal lack of O 2 and misfires, therefore, triggering an FSA. Klein hypothesizes that since PD patients believe they are suffocating, they begin to experience PA symptoms such as: shortness of breath, and hyperventilation in order to keep CO 2 levels well below the suffocation threshold. This implies that hyperventilation is a consequence and acts as a defense response against panic onset instead of a cause of PA. Breathing mechanisms are considered to operate base on a widespread neutral network which involves the medulla, hypothalamus, limbic area, and cortex.

Dysfunction in the endogenous opioid system has a possible etiological mechanism in PD and was proposed by Preter and Klein ( 78 ). In particular, it has been suggested that such dysfunction is mechanistically associated with decreases in the threshold of the suffocation alarm. This hypothesis was supported by the findings of Preter and colleague, who demonstrated that lactate infusions in naloxone-treated healthy participants produced feelings and symptoms which mimic those of PAs ( 79 ).

Research by Preter and Klein ( 83 ) conclusively showed a physiological link between panic-like suffocation in healthy adults and endogenous opioid system deficiency. According to Preter and Klein, episodic dysfunction of the opioidergic systems leads to a decreased threshold of the suffocation alarm, thereby producing PAs ( 25 , 84 ). Graeff proposed that endorphins increase suffocation sensitivity and separation anxiety in sufferers of PD increasing their vulnerability to experiencing PAs ( 14 ). The internal homeostatic milieu comprised of tight parameters involving pH homeostasis and chemosensation remain an important area of study that furthers our understanding of the pathophysiology and treatment of panic disorder. PAs have been conceptualized as resulting from dysfunction of 5-HT inhibitory projections to dorsal regions of DPAG that detect and process threat that is within close proximity, innate fear, or hypoxia. A faulty interaction between serotonin and opioid receptors in the DPAG has been associated with the onset of PAs ( 14 ). Hypoxia can be considered as an acute interoceptive threat activating a panic attack as circa strike defense which involves fight, flight, or freezing responses ( 31 ).

The ventral respiratory nuclei in the medulla plays a significant role in respiratory drive, which control the phrenic nerve activity as well as the sense of pH and CO 2 levels in the cerebrospinal fluid ( 85 , 86 ). Schenberg postulates that the SFA hypothesis presumes that the gas sensors that sense pH levels and CO 2 levels changes, and the suffocation alarm system may be utilizing different neural pathways ( 14 , 25 ).

A number of studies have highlighted PD patients experiencing a dysregulation of respiratory physiology ( 87 – 89 ). Respiratory abnormalities are noted in particular in participants with PD as compared to healthy controls and other anxiety disorders ( 90 ). In this study, the comparison between groups showed that PD differed with Social Phobia and Generalized Anxiety Disorder, where they demonstrated at baseline, lower end-tidal CO 2 pressure and a higher mean respiration rate. Furthermore, PD group exhibit lower venous CO 2 pressure and higher in the bicarbonate ion concentrations compared to other anxiety groups. Such unique baseline respiratory abnormalities and the chronic hyperventilation have been characterized to be specific of PD pathophysiology when compared to other anxiety disorders ( 91 ).

PD commonly co-occurs in patients with respiratory abnormalities ( 91 ). Indeed, the lifetime prevalence of respiratory disorders including chronic obstructive pulmonary disease (COPD) and asthma among patients suffering from PD is estimated to be 47% ( 92 ). There has been suggestion that the central part of PD is the respiratory dysfunction according to reports of high comorbidity between PD and respiratory abnormalities, ( 93 ). Moreover, research findings speculate that there may be a familial link between PD and COPD ( 94 ). A study suggests that 37 % of primary care outpatients suffering from COPD with depressive symptoms also had comorbidity of anxiety symptoms as well ( 95 ). Hyperventilation has been known to activate symptoms such as numbness, tingling sensations, dizziness, and muscle hypertonicity. These symptoms are consistent to hypocapnia and respiratory alkalosis, which results from an increased gas exchange in the lungs ( 96 ).

In particular, ample theoretical and empirical evidence links hyperventilation to anxiety and panic. Low CO 2 levels can occur even in the absence of functional breathing disorders due to the highly soluble nature of CO 2 (being twenty times more soluble than O 2 ). Stress, anxiety, and panic states can cause hyperventilation which leads to the depletion of CO 2 ( 97 ) and results in reduced cerebral blood flow and increased neuronal excitability ( 82 ). Intracellular pH and cellular metabolism and the regulation of cerebro-spinal fluid pressure can be disrupted or impaired ( 78 ). Hypocapnia produces bronchoconstriction in the lungs and vasoconstriction in the blood vessels ( 78 ). Adverse effects can also result in blood pressure, myocardial contractility, cardiac blood flow, pH regulation and electrolyte balance. Unsurprisingly, the association between breathing dysfunction and hyperventilation was established given the hyperventilation theories and evidenced by the extensive physiological effects of hypocapnia and the consequences of respiratory alkalosis, ( 98 ) supports to explain panic.

The respiratory subtype of PD, was identified by Briggs, Stretch, and Brandon (1993) and was characterized by prominent respiratory symptoms in PD patients. The prevalence rate of dysfunctional breathing in the general population has been as high as 5–11% ( 99 – 103 ). In asthma sufferers, it as high as 30% ( 104 ) and in anxiety sufferers as high as 83% ( 76 ). Consistent with previous findings, respiratory subtype has been correlated with high CO 2 sensitivity ( 105 – 108 ). Furthermore, an altered level of CO 2 sensitivity in the respiratory PD subtype has been identified in response to panic provocation challenges including the CO 2 challenge and breath-holding ( 108 – 110 ). Respiratory abnormality in PD is extensive and widely supported by research and propose that PAs result from respiratory abnormalities instead of fear and anxiety alone ( 30 , 111 – 113 ).

Summary of biological theories

In summary, the biological theories have provided well-grounded comprehension into discerning the pathophysiology and etiology of PD. Whilst biological theories have informed psychopharmacological treatments that have been successful in treating panic attacks ( 114 , 115 ), there are a number of emerging trends from the biological area. The empirical and clinical evidence suggests that first-line psychopharmacological treatments for PD include SSRI's and benzodiazepines. The former is best accompanied by CBT and the latter used short-term to manage PD symptoms ( 116 ). Dubovsky and Marshall in their review corroborates evidence contrary to the trend in prescribing patterns favoring SSRI's over BZ in anxiety treatment ( 116 ). Nardi and Quagliato suggest the need to reassess the use of BZ in long term treatment of panic vs. short term, as a number of patients may benefit from BZ as first-line treatment ( 117 ). A recent review evaluating therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) did not confirm the therapeutic potential for PD ( 118 ).

Furthermore, biological theories have been limited in terms of their utility in the development of treatments outside of psychopharmacology. In terms of efficacy, cognitive theories, particularly driven and informed by the development of Cognitive Behavioral Therapy (CBT), have gained greater acceptance as being better in treating and managing PD ( 119 , 120 ), which appears to be the preferred choice for a first line treatment. This is evidenced by participants in studies without a control condition despite being on a therapeutic dose of medication, have demonstrated improvement following the introduction of CBT ( 121 , 122 ). Several treatment studies have also shown that both short term and long-term behavioral therapy which aim to reduce one's adverse response to interoceptive and exteroceptive triggers may be equally effective as cognitive therapy in reducing panic disorder ( 123 , 124 ).

Cognitive theories

The cognitive-behavioral model of panic disorder identifies key factors that maintain panic disorder ( 120 ). The latest composite model of panic adopted several theories into one to explain causality ( 3 ). Earlier cognitive theory by Clark suggests that development and maintenance of PD is proposed to begin from the first PA, which most often occurs during a time of stress and is accompanied by “catastrophic misinterpretations” of somatic and other sensations as key ( 121 – 124 ). Irrespective of the source of an individual's internal physical sensations, an individual could develop panic, which in turn leads to catastrophic thoughts about their impending doom, such as “I am going to die”, or “I am having a heart attack”. The catastrophic thoughts sustain the vicious cycle, where anxiety provoking thoughts produce further somatic symptoms and continues the cycle of catastrophic thinking, thus inevitably ends in a PA. Internal focus on somatic and physical sensations has been linked to persistent vigilance and hypersensitivity to normal and common symptoms ( 125 ).

An element of self-efficacy was added into the vicious cycle where it is argued that an individual's negative perception of their coping abilities against threat also acts as a perpetuating factor to PA ( 3 ). The self-efficacy was perceived as parallel yet simultaneous in sustaining the vicious cycle. According to this particular cognitive model, one's low self-esteem results in high arousal which begins the panic cycle.

Cognitive and personality factors have been implicated ( 126 – 128 ) to place individuals at risk for the vigilance and misappraisals. In particular, “anxiety sensitivity” has been touted as one such vulnerability factor ( 129 ). The success of cognitive therapy PD treatment provides support for the misappraisal theory (e.g., Clark et al.). Further evidence has been demonstrated whereby hypothetical stimulations of catastrophic thinking, for instance by reading paired word combinations related to bodily sensations and catastrophes (e.g., “palpitations – die” and “breathless – suffocate”) has been found to increase the likelihood of panic attacks ( 122 ).

On the other hand, reduced catastrophic cognitions lead to a reduced probability of panic as a response to panic provocation as well ( 123 ). Whilst support for cognitive explanations of PD is present, Bouton and colleague notes two problems with regard to this approach ( 125 ). Catastrophic cognitions are often found to occur in clients with panic. Although, their causal relationship in creating panic attacks is unclear, the maintenance of PD is sustained by such catastrophic cognition as PD sufferers rely in safety seeking behavior and avoid and/or escape situations where panic occurs ( 130 ). Further support for the cognitive theory is evidenced by a causal relationship between bodily sensations and fearful cognitions ( 131 ). While the notion of nocturnal panic was once considered as being representative of support for a biological model of panic, such considerations failed to account for the selective and automatic or subliminal information processing that occurs during sleep ( 132 – 134 ).

CBT for PD patients promotes the development of self-efficacy which has been found to play an important part in defining the outcome of PD treatment ( 135 ). Research findings stipulate that a lack of self-efficacy in managing and dealing with PAs and misinterpretations of bodily sensations experienced during PAs are significant factors that affects treatment resistance PD ( 135 – 140 ). According to Barlow et al. ( 141 ), the evidence shows psychological treatments considered as more enduring after treatment termination, although pharmacological and psychological treatment have strongly demonstrated to produce equally effective treatment. Research suggests preferred strategy of PD treatment to be CBT or pharmacotherapy ( 11 ).

NICE guidelines for the treatment and management for PD includes shared decision-making and provision of information between healthcare professional and the client. This includes providing evidence-based information about PD (nature, course, treatment), discussing possible concerns around medication, taking into consideration client's prior experience with treatment, information regarding self-help groups and support groups, use of jargon-free language and accommodating to the client's language needs (translator, therapist proficient in client's preferred language) ( 142 ). These are important components to CBT as they facilitate necessary cognitive changes to impactors such as self-image, self-efficacy and literacy about panic attacks and other mental health issues.

Furthermore, as anxious individuals demonstrate deficits in inhibitory regulation and extinction learning, recent research has supported more optimal exposure strategies ( 16 ) that could easily be integrated into existing PD protocols. Inhibitory models support the linking of experiences during exposure that weaken anxiogenic associations. Moreover, the exposure facilitates a mismatch between client's expectations about their feared outcomes and their non-occurrence. Selective attention and cognitive biases also need to be targeted in successful treatment. As anxious individuals may try to distract or distance themselves from feared outcomes, therapists will typically direct attention back onto the fear during exposure and encourage consolidation of learning following the exposure. This will also augment the client's ability to retrieve any new linkages and discourage the return of the fears ( 16 ). As inhibitory associations are context-dependent, whereas excitatory associations are not ( 143 ), research has supported the need in exposure to include a variety of contextual, external or situational, internal (e.g., physiological, memory or other cognitive) and safety cues or triggers, inclusive of variability of within-exposure fear levels, in order to facilitate greater generalization and maintenance of gains. Hence, rather than relying on a behavioral habituation framework to conduct treatment, the inhibitory learning model additionally supports exposure from a planned hierarchy in a random order ( 16 ). Moreover, through its impact on expectancy violations, the inhibitory learning model supports the use of exposures where the feared outcome eventuates or is thought to eventuate. Such variations are often particularly useful in the later stages of CBT. For treatment-resistant panic disorder, the combination of CBT and pharmacotherapy is recommended as a secondary line of treatment strategy ( 11 ). When deciding the most optimal PD treatment strategy, individual characteristics of PD patients should be considered. Some patients may, for instance, be unable to tolerate the side effects of PD medications, therefore, proceeding with CBT may be beneficial whilst implicating pharmacotherapy may be better suited for patients with physical rather than cognitive symptoms of PD ( 11 , 144 – 148 ). The development of personalized models of intervention would support a treatment formulation that incorporated individual factors guiding clinical management.

Combination of psychological and biological factors

Some attempts have been made to compose a more integrative aetiological framework for PD. Learning theory by default integrated biological and psychological perspectives ( 125 ), whilst threat processing combined brain and mind-based theory and evidence ( 149 ). Pilecki et al. ( 8 ) scrutinized the model Fava and Morton proposed of applied causal modeling which aimed to link different components derived from biological and psychological theories ( 3 , 8 ). A major criticism was that equal weight on the model was given to psychodynamic theories of PD ( 150 ), even though there is minimal empirical support in comparison to cognitive theories. On the contrary, anxiety sensitivity theory ( 151 ) is given little weight in the Fava and Morton ( 3 ) model, despite substantial evidence consistent with a causal link in the onset of PD ( 152 ). On another note, there has been little development of evidence-based approaches for combined biological-psychological treatments for PD, particularly for treatment resistant or refractory presentations ( 153 ). Multidimensional models that identify and clarify the multi-level causal mechanisms are needed to assist with the integration of biological and psychological theories and approaches ( 154 ). Kendler ( 155 ) proposed framework which integrated and synthesized information from across multiple levels of function impacted by PD and agoraphobia, demonstrates the importance of understanding of how individual risk factors and their interactions alter the outcome of a clinical phenotype ( 132 ).

PD is conceptualized to be aetiologically complex, with risk determined by the interaction of multiple genetic and non-genetic risk factors spanning multiple levels of function which include biological/genetic, psychological, social, and cultural/economic ( 156 ). A summary of the theories discussed above can be seen in Table 1 . The several abovementioned biological theories have been explored to explain the etiology of PD, focusing on metabolic, hormonal, genetic, neurochemical, respiratory and hyperventilation factors. Amongst the most recent approaches are the neuroscientific theories which have involved insights from neuroimaging, and translational models of animal research. Animal studies have assisted with providing added knowledge of the current fear circuitry in the brain. Whilst translating animal models of neural systems responsible for learned fear responses contributes to an understanding of PD in humans, we are far from having a satisfactory explanation of the causes and mechanisms of PD ( 31 ). Psychological theories have also been prominent, particularly cognitive behavioral models, given their superior efficacy in treatment. A number of biological and psychological factors may act as precipitating factors toward increased vulnerabilities and affects the individual's susceptibility to the development of PD, and heightened sensitivity toward and false catastrophic interpretation of psychophysiological sensations play a key role in the maintenance of the disorder. Cognitive behavioral and biological approaches that considers physiological and psychological factors interaction are likely to integrate relevant research findings that supplement of the advancement of more efficacious PD treatments. Indeed, the role of combination therapy, whereby psychological and pharmacological treatment modalities are used synergistically has been shown to have advantages in the treatment of PD ( 157 , 158 ), although there may also be disadvantages particularly with respect to the impact of pharmacotherapy on developing adaptive appraisals. Three studies investigating the efficacy of CBT alone or combined CBT and pharmacotherapy found that compared to combined treatment, CBT alone produced superior results, with the studies indicating that the effects of CBT were found to be durable and long-lasting post-treatment ( 2 , 155 , 159 – 161 ). Upon treatment discontinuation, combined treatment of CBT and pharmacotherapy has been associated to greater rates of relapse ( 162 ).

Table 1 . The summary of theories explaining the etiology of PD.

Further understanding of the complex underlying mechanisms of PD needs to be supported not only by scientific insights into the biological factors but also other factors such as the genetic and epigenetic factors in relation to neurochemical, respiratory, endocrine, cognitive and behavioral systems. A multifactorial approach and model for PD may also contribute to the development of pioneering treatments which possibly targets physiological, cognitive, and behavioral symptoms of anxiety and panic.

Author contributions

PK contributed to the conceptualization, writing, reviewing, and editing of the article. MK provided editing and review. Both authors contributed to the article and approved the submitted version.

Acknowledgments

PK wants to acknowledge that parts of this paper were taken from his dissertation. Citations and reference are stated accordingly.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

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Keywords: panic disorder, etiology, biological theories, psychological theories, narrative review

Citation: Kyriakoulis P and Kyrios M (2023) Biological and cognitive theories explaining panic disorder: A narrative review. Front. Psychiatry 14:957515. doi: 10.3389/fpsyt.2023.957515

Received: 31 May 2022; Accepted: 04 January 2023; Published: 30 January 2023.

Reviewed by:

Copyright © 2023 Kyriakoulis and Kyrios. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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4 The Genetics of Anxiety Disorders

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Family and twin studies have established that anxiety disorders are familial and moderately heritable. Approximately 20–40% of the risk of anxiety disorders is attributable to genetic variation in the population. In recent years, molecular genetic methods have been applied to search for the genes underlying anxiety disorder heritability, with limited success to date. Several candidate genes have been implicated in risk of anxiety disorders, anxiety-related traits, and anxiety-related brain phenotypes, but results have been inconsistent. No specific common or rare variants have been established by genome-wide association studies. Anxiety disorders are likely to be highly polygenic. Genetic influences are shared across a range of anxiety disorders and depression. Success in identifying risk loci and gene-environment interactions will require much larger samples and should capitalize on insights from animal models human studies of anxiety-related brain circuitry.

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• Dtsch Arztebl Int
• v.115(37); 2018 Sep

The Diagnosis and Treatment of Anxiety Disorders

Andreas ströhle.

1 Department of Psychiatry and Psychotherapy, Campus Charité Mitte (CCM), Charité—Universitätsmedizin Berlin

Jochen Gensichen

2 Institute of General Practice, Faculty of Medicine, Ludwig-Maximilians-Universität München

Katharina Domschke

3 Department of Psychiatry and Psychotherapy, University Hospital of Freiburg

Anxiety disorders are the most common type of mental illness in Europe, with a 12-month prevalence of 14% among persons aged 14 to 65. Their onset is usually in adolescence or early adulthood. The affected patients often develop further mental or somatic illnesses (sequential comorbidity).

This review is based on pertinent publications retrieved by a selective search in PubMed.

The group of anxiety disorders includes generalized anxiety disorder (GAD), phobic disorders, panic disorders, and two disorders that are often restricted to childhood—separation anxiety and selective mutism. A comprehensive differential diagnostic evaluation is essential, because anxiety can be a principal manifestation of other types of mental or somatic illness as well. Psychotherapy and treatment with psychoactive drugs are the therapeutic strategies of first choice. Of all types of psychotherapy, cognitive behavioral therapy has the best documented efficacy. Modern antidepressants are the drugs of first choice for the treatment of panic disorders, agoraphobia, social phobia, and GAS; pregabalin is a further drug of first choice for GAS.

In general, anxiety disorders can now be effectively treated. Patients should be informed of the therapeutic options and should be involved in treatment planning. Current research efforts are centered on individualized and therefore, it is hoped, even more effective treatment approaches than are available at present.

Anxiety is a a normal and necessary basic emotion without which individual survival would be impossible. Pathologically increased anxiety can arise not only in anxiety disorders per se, but also in most other types of mental illness. Anxiety can also be a warning signal of potential harm in somatic illnesses, such as myo-cardial infarction or hypoglycemia in a diabetic patient; it naturally requires an entirely different therapeutic approach in such situations. For any patient presenting with pathologically increased anxiety, a thorough psychiatric and somatic evaluation is needed so that an underlying pulmonary ( e1 ), cardiovascular ( e2 ), neurological ( e3 ), or endocrine disease (e.g., of the thyroid gland) ( e4 ) can be ruled out. Anxiety reactions as such are important indicators of a possible threat to homeostasis; anxiety is considered a disease requiring treatment when it arises in the absence of any threat, or in disproportionate relation to a threat, and keeps the affected individual from leading a normal life.

Anxiety disorders

Anxiety is considered a disease requiring treatment when it arises in the absence of any threat, or in disproportionate relation to a threat, and keeps the affected individual from leading a normal life.

Learning objectives

After reading this article, the reader should

• know that anxiety disorders are common mental illnesses of early onset that elevate the risk of developing further mental illnesses;
• understand the clinical manifestations of anxiety disorders;
• be aware of the current treatments of first choice.

Women are affected two to three times as commonly as men.

Epidemiology

Anxiety disorders are the most common type of mental illness in the European Union, Switzerland, Iceland, and Norway (figures for the year 2010). With a 12-month prevalence of 14% and approximately 61.5 million affected persons, they are more common than any other mental illness among persons in Europe aged 14 to 65. Women are affected two to three times as commonly as men ( 1 ).

Anxiety disorders often begin in childhood or adolescence ( e5 ). This is particularly true for specific phobias and social phobia. Selective mutism can arise as early as a child’s third year. Most children go through a transient phase of non-pathological aversion to strangers, often beginning at the age of eight or nine months. In 2–3% of children, marked separation anxiety persists into the preschool or school-age years. Treatment is indicated if separation anxiety impairs the normal development of the child, e.g., by making it impossible for the child to have important social experiences.

The World Health Organization (WHO) reported that, in 2015, anxiety disorders ranked in sixth place among all mental and somatic illnesses worldwide as a cause of so-called years lived with disability (YLD), and in fourth place in highly developed countries; they are thus among the chronic illnesses with the greatest impact on patients’ lives ( 2 ). Specific phobias are the most common type of anxiety disorder.

Taxonomy and manifestations

The anxiety disorders, as classified in the International Classification of Diseases (ICD-10) ( 3 ), comprise the phobic disorders, including agoraphobia with (F40.00) or without panic disorder (F40.01), social phobia (F40.1), and the specific phobias (F40.2), as well as other anxiety disorders, including panic disorder (F41.0), generalized anxiety disorder (F41.1), and mixed anxiety and depression (F41.2) ( table 1 ). In the current edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) ( e6 ), which is the main reference text for the taxonomy of mental illnesses in the USA, separation anxiety disorder and selective mutism are newly classified as anxiety disorders. These were previously considered illnesses restricted to childhood and adolescence, but are now held to be relevant in adulthood as well. The upcoming ICD-11 can be previewed in a beta version that is available online. In this classification, too, separation anxiety disorder and selective mutism will appear for the first time among the (adult) anxiety disorders ( 4 ).

Age of presentation

Anxiety disorders often begin in childhood, adolescence, or early adulthood.

Separation anxiety disorder is characterized by persistent and excessive anxiety associated with separation from the patient’s most significant other(s), to an inappropriate extent from the developmental psychological point of view. Its lifetime prevalence is 4.8%. It is usually initially diagnosed in childhood, but recent studies have shown that it is increasingly common in adulthood as well. For instance, an evaluation of the World Mental Health Survey conducted by the World Health Organization (WHO) revealed that, among 38 993 adults in 18 different countries, the age of onset of separation anxiety disorder was over 18 years in 43.1% of cases ( 5 , 6 ).

Selective mutism is a rare anxiety disorder that usually presents in childhood or adolescence. The diagnostic evaluation for this disorder often takes place only after the child has started school. Persons suffering from selective mutism are persistently unable to speak in certain situations, even though they can do so in other situations, usually when with their families. If the patient emits no phonetic expressions of any kind (e.g., coughing, crying, laughing, or speaking) in any situation whatsoever, the term “total mutism” is used. According to the DSM-5 ( e6 ), the point prevalence of selective mutism lies between 0.03% and 1%. No data are yet available from representative epidemiological studies of entire populations; the wide disparity of prevalence estimates is presumably due to the diversity of settings in which the data were acquired (hospitals, schools, the population at large) ( e6 ). Approximately one-third of sufferers have persistent symptoms into adulthood ( 7 ). Unfortunately, no valid data are available on the frequency of this disorder as a function of age.

Sequential comorbidity

Anxiety disorders elevate the risk of developing other mental illnesses.

Anxiety disorders are associated with high parallel comorbidity with other anxiety disorders. In addition, individuals with an anxiety disorder are at elevated risk of developing further anxiety disorders over time. A meta-analysis of 20 studies revealed that, among children with separation anxiety, the risk of developing a panic disorder later on is more than three times higher than in children without separation anxiety ( 8 ). The epidemiological term for such longitudinal associations is “sequential comorbidity” ( Figure ). This exists not only within the anxiety disorders among themselves, but beyond them as well: anxiety disorders elevate the risk of developing other mental illnesses such as depression or substance-related disorders ( 9 ). For example, a Danish study on a cohort of 3 380 059 persons showed that patients with anxiety disorders, in comparison to the general population, have an adjusted incidence rate ratio (IRR) of 3.0 for a depressive episode (95% confidence interval [CI]: [2.8; 3.1]) and an IRR of 5.0 for a recurrent depressive disorder (95% CI: [4.8; 5.2]) ( 10 ).

Anxiety disorders presenting early in life increase the risk of developing other mental illnesses later on in life (sequential comorbidity) (modified from [e7] and reprinted with the kind permission of John Wiley, publishers)

Anxiety disorders also play a major role in the development and prognosis of somatic diseases. In a longitudinal study of 293 persons (median age: 55 years) who were in good cardiovascular and autoimmune health, amygdalar activation on 18 F-fluorodexoyglucose positron emission tomography/computed tomography ( 18 F-PET-CT)—a key radiological finding that is typical of anxiety disorders—was found to be associated with an elevated risk of developing cardiovascular disease in a subsequent observation period of 3.7 years (median duration). There were a total of 22 new cases of cardiovascular disease and a calculated hazard ratio (HR) of 1.6 (95% CI: [1.27; 1.98]), i.e., a 60% elevation of the risk of developing a cardiovascular disease for each increase of the amygdalar signal by one standard deviation. This association seems to be mediated by elevated bone-marrow activity and arterial inflammation. When interpreting these results, one must bear in mind that amygdalar activation is a general measure of emotional processes and is not specific for anxiety or for anxiety disorders ( 11 ).

• Generalized anxiety disorder

This type of anxiety disorder manifests itself with anxious worrying, tension, and fears about everyday events and problems.

In a meta-analysis of 16 cohort studies (Health Survey for England [HSE], Scottish Health Survey [SHS]) involving a total of 163 363 men and women who stated that they did not have cancer at the time of inclusion in the study, it was found, after correction for age, sex, level of education, smoking status, and alcohol consumption, that persons with a high anxiety/depression score at the time of inclusion were significantly more likely to die of cancer in an ensuing observation period of 9.5 years (mean duration; 4353 deaths overall; multivariable adjusted hazard ratio 1.32, 95% CI: [1.18; 1.48]), compared to persons with a low anxiety/depression score (GHQ-12: 0–6). This was particularly the case for colorectal, prostatic, pancreatic, and esophageal cancer and for leukemia. Aside from other, possibly overlooked confounding variables, it cannot be ruled out that persons with a high anxiety/depression score at the time of inclusion already had an as yet undetected subclinical malignancy, leading to increased mental stress in the sense of what epidemiologists call “reverse causality.” To limit the influence of initially occult malignancies on the study findings, patients who died in the first five years of the observation period were excluded from the analysis ( 12 ).

The early detection and treatment of anxiety disorders may thus have a secondary preventive effect against further mental and somatic diseases as well as a beneficial influence on the course of somatic disease. The association between early detection and prevention remains to be examined in randomized controlled trials.

Panic disorders are characterized by:

Repeated and unexpected panic attacks (anxiety attacks) with both physical manifestations (palpitations, dyspnea, diaphoresis, paresthesiae, nausea) and mental ones (fear ranging to mortal fear, fear of losing control, feeling of alienation).

Anxiety disorders are among the so-called complex genetic diseases characterized by a complex pathogenetic interaction of environmental factors with multiple genetic variants at different chromosomal loci. Family studies have shown that first-degree relatives of patients with panic disorders have a three- to fivefold elevation of the risk of developing such a disorder themselves, compared to the general population. Familial clustering is also seen in generalized anxiety disorder and in the specific phobias. The heritability of anxiety disorders, i.e., the degree of participation of genetic factors in their development, lies in the range of 30–67%, with the remainder of the variation accounted for by individual negative environmental factors, such as life events ( 13 ). These include, for example ( 14 ):

• Abuse and neglect (emotional and/or physical)
• Sexual violence
• Chronic illness
• Traumatic injuries
• Deaths of significant others
• Separation and divorce
• Financial difficulties.

On the other hand, positive environmental factors, effective coping strategies, secure bonding styles, supportive learning experiences, and a good social support network can increase resilience, even in the presence of a genetic risk-factor constellation. Meanwhile, the role of epigenetic mechanisms in the causation of anxiety disorders is gaining increased attention. Epigenetic mechanisms are biochemical processes, such as, for example, DNA methylation or histone acetylation, that act on DNA or its spatial structure without changing the DNA sequence per se. They play an important role in the regulation of gene activity and display marked temporal plasticity, being alterable by life events or even by psychotherapeutic intervention. Epigenetic processes may, therefore, play a key role in tipping the balance between risk factors and resilience, leading to an adaptive or maladaptive outcome: it is perhaps the integration of the genetic risk together with the environmentally determined risk by way of epigenetic processes that ultimately determines whether an anxiety disorder will arise. Individual epigenetic effects, like individual genetic effects, are small ( 15 ). Initial epigenetic pilot studies on small groups of patients with anxiety disorders have revealed altered patterns of DNA methylation in risk genes for these disorders, and it seems that successful psychotherapy or pharmacotherapy leads to the normalization of these altered epigenetic patterns ( 16 ).

Genetic factors

The heritability of anxiety disorders, i.e., the degree of participation of genetic factors in their development, lies in the range of 30–67%, with the remainder of the variation accounted for by individual negative environmental factors, such as life events.

The neuronal structures that participate in the anxiety network include the amygdala, whose efferent fibers to the hypothalamus, the locus ceruleus, and the periaqueductal gray play a role in the regulation of the central and peripheral manifestations of the anxiety response, and areas of prefrontal cortex and the anterior cingulate gyrus that exert an inhibitory effect on the amygdala ( 17 , 18 ). Further brain areas belonging to the anxiety network are the insula, which integrates interoceptive signals, and the bed nucleus of the stria terminalis, which has recently been ascribed a central role in what is called “sustained anxiety”—a typical feature of generalized anxiety disorder, panic disorder, and social anxiety disorder ( 19 ).

Learning plays a major role in the development and maintenance of anxiety disorders, as well as in their treatment. Classical and operant conditioning exert their effects, and avoidant behavior contributes to the maintenance of the disorder. There also seems to be an evolutionarily determined capacity to mount an excessive anxiety reaction to the objects of the specific phobias, encouraging the development of these phobias; Seligman introduced the term “preparedness” for this capacity ( e8 ). Personality traits, too, especially neuroticism, are related to the development of anxiety disorders ( e9 ). Extinction learning via in-vivo exposure is now considered to be a form of relearning, rather than the erasure (unlearning) of previously acquired content.

As recommended in the S3 guideline on the treatment of anxiety disorders issued in May 2014 ( 20 ), psychotherapy and pharmacotherapy should both be offered, and the two are considered comparably effective. Decisions about treatment should be made in the light of the severity of the disorder, the preference of the informed patient, the expected latency and durability of the treatment effect, the expected side effects, and the availability of the treatment in question. If one form of treatment proves to be ineffective, the other (or a combination of both) should be tried. Only for the specific phobias is there very good evidence, and therefore a very strong recommendation, for psychotherapy alone; drugs are not indicated in the treatment of the specific phobias.

Anxiety disorders can be treated with psychotherapy, drugs, or both.

For all types of anxiety disorder, cognitive behavioral therapy is the type of psychotherapy for which there is the strongest evidence and which receives the highest-level recommendation (Ia; A). Initial randomized controlled trials have confirmed the clinical efficacy of psychodynamic therapies, e.g., in social phobia ( 21 ). Nonetheless, psychodynamic therapy receives evidence level IIa in the current German guidelines because of the incomplete state of the data from clinical trials, along with the recommendation that this type of psychotherapy should be offered if cognitive behavioral therapy has been ineffective or is unavailable, or if an informed patient expresses a preference for it ( 20 ). The specifics of cognitive behavioral therapy vary depending on the particular anxiety disorder being treated, with the common element that the patient must make the experience that his or her situationally induced anxiety is unfounded and the situation actually harmless. This is best achieved through exposure under the supervision of a therapist ( 22 ), in the course of which the patient must experience habituation of the anxiety response, so that the central fear underlying it is refuted. Exposure in virtual reality is now increasingly a part of cognitive-behavioral therapeutic interventions ( 23 ).

Psychotherapy

Cognitive behavioral therapy is the tpe of psychotherapy of first choice in the treatment of the anxiety disorders.

Cognitive behavioral therapy has been found to have a moderately strong beneficial effect against all types of anxiety disorder compared to a placebo drug (Cohen’s d = 0.57); the same is true of pharmacotherapy (e.g., sertraline, d = 0.54; venlafaxine, d = 0.50) ( 24 ). If only the before vs after changes are studied, remarkably strong effects are found for pharmacotherapy (selective serotonin and norepinephrine reuptake inhibitors [SNRI], d = 2.25) compared to cognitive behavioral therapy (d = 1.30) ( 24 ). Combining pharmacotherapy with psychotherapy is usually not superior to monotherapy with either one of the two options alone ( 20 ). In a meta-analysis of the few available studies with long follow-up periods, Bandelow et al. ( 25 ) concluded that further symptomatic improvement took place 26–104 weeks after the end of cognitive behavioral therapy. After pharmacotherapy, there was no worsening in the follow-up period, but this difference compared to cognitive behavioral therapy did not reach statistical significance.

The drugs with the highest level of supporting evidence are the selective serotonin reuptake inhibitors (SSRI) and SNRI, as well as the calcium-channel modulator pregabalin for generalized anxiety disorder ( table 2 ).

* 1 according to the German guidelines

* 2 Case studies indicate that pregabalin has a potential for abuse. mainly in patients with substance-related disorders and above all in opiate-dependent patients ( 26 ). It is accordingly recommended in the German guidelines that patients with substance-related disorders. and particularly those who are addicted to multiple drugs. should not be treated with pregabalin. If a patient does not respond to a drug or cannot tolerate it. the next step may be a switch from one standard drug to another (e.g.. from an SSRI to an SSNRI; in generalized anxiety disorder. from an SSRI to pregabalin) or a switch to a nonstandard drug. such as one with a lower evidence level or recommendation grade (e.g.. moclobemide in social phobia). or to one that is not approved for the treatment of anxiety disorders. but has ?nonetheless been reported to be clinically effective (e.g.. quetiapine. agomelatine. lavender oil. and. in some cases. mirtazapine).

CCP = clinical consensus point; SSRI = selective serotonin reuptake inhibitors; SNRI = selective serotonin and norepinephrine reuptake inhibitors;

MAO = monoamine oxidase; TZA = tricyclic antidepressants

Treatment with psychoactive drugs

The drugs most commonly used are the selective serotonin reuptake inhibitors (SSRI) and the selective noradrenaline ruptake inhibitors (SNRI).

In the informed-consent discussion, the patient should not only be informed of the specific side effects of the drug class(es) to be prescribed, but should also be told that the effect of antidepressant drugs may be delayed by a latency of approximately two weeks (range: 1–6 weeks), and that these drugs may, in fact, initially worsen nervousness, agitation, and anxiety. They should therefore be given at a low dose at first, with gradual upward titration ( box ).

The off-label use of drugs that have not been approved for the treatment of anxiety disorders

The atypical antipsychotic drug quetiapine has not been approved for the treatment of anxiety disorders. Still, a meta-analysis of three randomized, double-blind, placebo-controlled trials of this drug for the treatment of generalized anxiety disorder (GAD), given for a period of 10 weeks in each trial, showed that it is significantly more effective than placebo in the 50 to 300 mg/day dose range, albeit with an unfavorable profile of metabolic side effects ( e10 ).

Agomelatine acts as an agonist at melatonin MT1- and MT2-receptors and as an antagonist at the serotonin 2C receptor. Multiple studies published from 2008 onward have shown it to be well tolerated and highly effective against GAD in the 25–50 mg/day dose range ( e11 ), yet this drug has not been approved for the treatment of anxiety disorders either.

Silexan, a patented active substance derived from lavender oil, has been approved since 2009 in Germany for the treatment of subsyndromal anxiety and tension states at a daily dose of 80 mg, but not for the treatment of anxiety disorders. Nonetheless, randomized controlled trials (RCTs) have shown its effectiveness against GAS and so-called mixed anxiety and depression ( e12 ).

A common question in clinical practice is how long drug therapy should be continued in order to prevent a relapse. The response rates are generally high (ca. 80%), but too early discontinuation of medication is associated with non-negligible relapse rates. Among patients with panic disorder, for example, a relapse is seen in 15–50% within 6–12 months of the discontinuation of tricyclic antidepressants, SSRI, or venlafaxine. It is therefore recommended that maintenance therapy with SSRI or SNRI be continued for at least 6–12 months after the end of the acute phase, at the effective final dose that was attained. Any attempt to discontinue medication should be gradual, e.g., over the course of 12 weeks if the duration of treatment until now has been 40 weeks ( 27 ).

Benzodiazepines are approved in Germany for the acute treatment of “states of tension, excitation, and anxiety.” Nonetheless, the German guidelines on the treatment of anxiety disorders discuss the use of benzodiazepines for this purpose in decidedly critical terms: “Benzodiazepines are effective against panic disorder/agoraphobia/generalized anxiety disorder/social phobia (Ia; guideline adaptation). They should nonetheless not be offered to patients with panic disorder/agoraphobia/generalized anxiety disorder/social phobia because of their serious side effects (development of dependence, etc.). They can be used for a limited time after careful evaluation of the risks and benefits in exceptional cases, e.g., patients with severe cardiac disease, contraindications for standard drugs, suicidality, and other conditions.“ The discontinuation of benzodiazepines after they have been taken for months or years, as is often the case, is a special challenge in the treatment of patients with anxiety disorders ( 28 ). Drug discontinuation must often take place in an inpatient setting, and only a few of the pertinent treatment recommendations are supported by adequate evidence.

• Benzodiazepines

Benzodiazepines are approved in Germany for the acute treatment of “states of tension, excitation, and anxiety.” Nonetheless, the German guidelines on the treatment of anxiety disorders discuss the use of benzodiazepines for this purpose in decidedly critical terms because of their marked side effects.

While cognitive behavioral therapy and psychopharmacotherapy are considered first-line treatments for anxiety disorders, further treatment strategies have been studied and applied in routine clinical practice in recent years, such as the following:

• Metacognitive therapy ( 29 )
• Acceptance and commitment therapy (ACT) ( 30 )
• Mindfulness-based techniques ( 31 )
• Noninvasive stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct-current stimulation (tDCS) ( 32 )
• Physical activity and exercise ( 33 ).

A systematic review of the literature is needed so that the relevance of new studies for the guideline recommendations can be appropriately assessed.

We find the use of physical activity and exercise as a treatment of anxiety disorders to be particularly interesting. This mode of treatment is inexpensive and has few undesired effects; it should be applied in combination with the first-line therapies (not as the sole intervention) and is used much too rarely in routine clinical practice ( 33 ). Very strong pre/post effect strengths of g = -1.23 ( 24 ) seem impressive but have not been reproduced in studies with active control groups ( 34 ). Even single units of endurance training can have an anxiolytic effect ( e13 – e15 ) or perhaps reinforce the effect of exposure therapy ( 35 ).

Aside from drug therapy of the types discussed, clinical practice guidelines also contain recommendations for psychological treatments of anxiety disorders in the primary medical care setting. The essential building-blocks of treatment are ( 20 ):

• counseling,
• psycho-education about anxiety and anxiety disorders,
• instructions for anxiety-confronting exercises in real-life situations, and
• the use of self-help manuals ( 20 ).

The essential components of the treatment of panic disorder with agoraphobia are:

• Psycho-education about anxiety and anxiety disorders
• Anxiety-confronting exercises in real-life situations
• Self-help manuals

The primary care physician and the patient work jointly to develop a gradually intensifying treatment plan (participative decision-making). With the primary care physician’s attentive personal support and counseling, the patient carries out specific anxiety-reducing exercises ( 36 ). Anxiety-confronting exercises are performed in controlled fashion according to the principles of cognitive behavioral therapy (CBT). Patients with panic disorder, in particular, are confronted with so-called interoceptive stimuli (as an exercise, including, for instance, 60 seconds of hyperventilation under supervision); patients with agoraphobia are confronted with so-called situational stimuli (e.g., taking a train ride by oneself). It is important for the patient to discuss the exercise afterward with the physician in order to reinforce the new experience and solidify the associated learning achievement. The stimuli that were originally felt to be anxiety-producing are now judged more appropriately. Trained medical practice assistants can serve as case managers to help the patient carry out these exercises: they telephone the patient regularly to record the patient’s current disease manifestations with the aid of a brief symptom checklist. This list is at the center of communication between the physician, the patient, and the practice assistant ( 37 ); it permits rapid assessment of the patient’s situation and reliable transmission of this information to the physician, who can then respond in timely fashion. If the symptoms fail to improve rapidly under the care of the primary care physician, a psychiatrist or psychotherapist should be consulted without delay. It has been shown that the ambulatory treatment of patients with panic disorder and agoraphobia with exposure therapy is more effective when carried out under direct supervision than when carried out by the patient alone according to directions ( 22 ). Supervision of the exposure places a heavy psychological demand on the therapist as well ( 38 ); this can be observed in the activation of the stress hormone system, particularly with massive exposure (flooding) ( 39 ).

Exercise therapy

Exercise has an anxiolytic effect and is therapeutically useful in both the short term and the long term.

Panic disorders

Patients with panic disorder, in particular, are confronted with so-called interoceptive stimuli (as an exercise, including, for instance, 60 seconds of hyperventilation under supervision); patients with agoraphobia are confronted with so-called situational stimuli (e.g., taking a train ride by oneself).

Exposure under the supervision of a therapist

It has been shown that the outpatient treatment of patients with panic disorder and agoraphobia with exposure therapy is more effective when carried out under direct supervision than when carried out by the patient alone.

The development and assessment of preventive measures against anxiety disorders should have a high priority in view of these disorders’ high prevalence and chronicity, the severity of the suffering that they cause, their high socioeconomic costs, and their role as precursors of depression and substance-abuse disorders and as complicating factors in somatic disease ( 40 ). Universal preventive measures, applied regardless of the risk status of the individual, might prevent many cases of clinically manifest anxiety disorders, even if their individual effects were not very strong; yet their application to large, unselected target groups would be both very expensive and very labor-intensive. The alternative lies in targeted programs, or, in other words, selective primary preventive measures, such as the Cool Little Kids program or the Friends program. These measures are particularly effective in preventing the development of clinically overt anxiety disorders in high-risk groups in the critical temporal window of childhood and adolescence. For example, a longitudinal randomized controlled trial showed that the Cool Little Kids program was significantly superior to control (no treatment) in a population of 3- to 5-year-old preschool children: the preventive intervention significantly lowered the incidence of anxiety disorders at 12 (p = 0.03), 24 (p = 0.03), and 36 (p = 0.01) months, and even after a further follow-up period of 11 years—but then only among the girls, who were about 15 years old by that time (Cohen’s d = 0.55, p = 0.04) ( e16 , e17 ). Targeted prevention in persons who already display subclinical symptoms has been shown to significantly lessen the rate of development of clinically relevant anxiety disorders and is thus probably the most cost-effective primary measure. Meta-analyses have revealed low effect strengths for the prevention of anxiety; targeted measures were found to be somewhat more effective than universal ones right after the intervention (Cohen’s d = 0.26 versus 0.17 [e18, e19]). The prevention manuals now available in the German-speaking countries include, for example, the Friends program; the Separation Anxiety Program for Families ( Trennungsangstprogramm für Familien, TAFF); the Being Brave with Til Tiger program (Mutig werden mit Til Tiger); and the Health and Optimism Program (Gesundheits- und Optimismus-Programm). The encouraging initial data imply that preventive measures against mental illnesses, and in particular against anxiety disorders, which are very common and socioeconomically relevant, urgently need to be studied further, systematically, and in detail. If their effects can be confirmed, these measures should be implemented in timely fashion in the healthcare system.

Prevention manuals

The prevention manuals now available in the German-speaking countries include, for example, the Friends program; the Separation Anxiety Program for Families (TAFF); the Being Brave with Til Tiger program; and the Health and Optimism Program.

Further information on CME

• Participation in the CME certification program is possible only over the Internet: cme.aerzteblatt.de. This unit can be accessed until 9 December 2018. Submissions by letter, e-mail or fax cannot be considered.
• Arterial Hypertension” (issue 33–34/2018) until 11 November 2018,
• Drug Hypersensitivity” (issue 29–30/2018) until 14 October 2018.
• This article has been certified by the North Rhine Academy for Continuing Medical Education. Participants in the CME program can manage their CME points with their 15-digit “uniform CME number” (einheitliche Fortbildungsnummer, EFN), which is found on the CME card (8027XXXXXXXXXXX). The EFN must be stated during registration on www.aerzteblatt.de (“Mein DÄ”) or else entered in “Meine Daten,” and the participant must agree to communication of the results.

CME credit for this unit can be obtained via cme.aerzteblatt.de until 9 December 2018.

Only one answer is possible per question. Please choose the most appropriate answer.

What is the approximate 12-month prevalence of anxiety disorders among 14- to 65-year-olds in Europe?

•  5%

What is the most common type of anxiety disorder?

• Selective mutism
• Panic disorder
• Specific phobia
• Social phobia

What percentage of the development of anxiety disorders is accounted for by genetic factors?

• 1–27%
• 30–67%
• 40–77%
• 50–87%
• 60–97%

What type of psychotherapy is the treatment of first choice for anxiety disorders?

• Psychoanalysis
• Cognitive behavioral therapy
• Psychodynamic psychotherapy
• Talk psychotherapy
• Eye movement desensitization and reprocessing (EMDR)

What psychoactive drug(s) is/are the first line of drug therapy for anxiety disorders?

• Selective serotonin
• (and norepinephrine) reuptake inhibitors
• Neuroleptic drugs
• T tricyclic antidepressants

Which of the following substances is effective against generalized anxiety disorder, according to clinical trials, but not approved for this purpose in Germany?

• Lavender oil extract
• Oil of St. John’s wort
• Ginger extract
• Thyme extract
• Sage extract

What is a typical feature of a panic disorder?

• Panic attacks arise exclusively in certain situations.
• Panic attacks begin unexpectedly.
• The patient has a constant feeling of panic.
• The patient complains of persistent worry.
• Hypochondriac fears are expressed.

What type of complementary treatment can be used beneficially in patients with anxiety disorders?

• Bioresonance tomography
• Aggression training
• Physical activity and exercise
• Bach blossom therapy

How long after the end of the acute phase of successful drug treatment for panic disorder should the drug be continued for maintenance therapy?

• 1 to 3 months
• 3 to 6 months
• 6 to 12 months
• 12 to 18 months
• 18 to 24 months

Question 10

What is a typical feature of selective mutism?

• It is a disease of old age.
• The patient has a marked fear of bodily contact.
• Girls of pubertal age are often affected.
• The patient cannot speak in certain situations.
• The patient cannot make eye contact.

Acknowledgments

Translated from the original German by Ethan Taub, M.D.

Conflict of interest statement

The authors declare that no conflict of interest exists.

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The Separation Anxiety Hypothesis of Panic Disorder Revisited: A Meta-Analysis

• Joe Kossowsky , Ph.D. ,
• Monique C. Pfaltz , Ph.D. ,
• Silvia Schneider , Ph.D. ,
• Jan Taeymans , Ph.D. ,
• Cosima Locher , B.Sc. , and
• Jens Gaab , Ph.D.

Search for more papers by this author

Evidence suggests that childhood separation anxiety disorder may be associated with a heightened risk for the development of other disorders in adulthood. The authors conducted a meta-analysis to examine the relationship between childhood separation anxiety disorder and future psychopathology.

PubMed, PsycINFO, and Embase were searched for studies published through December 2011. Case-control, prospective, and retrospective cohort studies comparing children with and without separation anxiety disorder with regard to future panic disorder, major depressive disorder, any anxiety disorder, and substance use disorders were included in the analysis. Effects were summarized as pooled odds ratios in a random-effects model.

Twenty-five studies met all inclusion criteria (14,855 participants). A meta-analysis of 20 studies indicated that children with separation anxiety disorder were more likely to develop panic disorder later on (odds ratio=3.45; 95% CI=2.37–5.03). Five studies suggested that a childhood diagnosis of separation anxiety disorder increases the risk of future anxiety (odds ratio=2.19; 95% CI=1.40–3.42). After adjusting for publication bias, the results of 14 studies indicated that childhood separation anxiety disorder does not increase the risk of future depression (odds ratio=1.06; 95% CI=0.78–1.45). Five studies indicated that childhood separation anxiety disorder does not increase the risk of substance use disorders (odds ratio=1.27; 95% CI=0.80–2.03). Of the subgroup analyses performed, differences in comparison groups and sample type significantly affected odds ratio sizes.

Conclusions

A childhood diagnosis of separation anxiety disorder significantly increases the risk of panic disorder and any anxiety disorder. These results support a developmental psychopathology conceptualization of anxiety disorders.

Separation anxiety disorder is characterized by persistent, excessive, and developmentally inappropriate fear of separation from major attachment figures, usually parents ( 1 ). It is one of the most frequently diagnosed childhood anxiety disorders, with lifetime prevalence rates between 4.1% and 5.1% ( 2 , 3 ).

Suggestions of a specific link between separation anxiety in childhood and adult panic disorder can be found in the early work of Klein ( 4 ), who noted that imipramine blocked the key panic attacks in patients hospitalized for agoraphobia. Review of the patients’ histories indicated that those with early onset also had separation anxiety. Klein’s separation anxiety hypothesis stimulated much research leading to ambiguous results. At present, the consequences of childhood separation anxiety disorder for future mental disorders are not clear. Some studies have identified it as a specific risk factor for adult panic disorder ( 4 ), others have identified it as a general risk factor for multiple adult anxiety and nonanxious disorders ( 5 – 7 ), and yet others have demonstrated that it may continue into adulthood ( 8 ).

One of the first attempts to review the literature on the relationship between separation anxiety disorder and mental disorders in adulthood was by Silove et al. ( 9 ), who analyzed the early evidence for an association between childhood separation anxiety disorder and adult panic disorder with agoraphobia. They concluded that there was evidence supporting the link, although the specificity of that relationship required further clarification. However, they focused exclusively on the link between separation anxiety disorder and panic disorder with agoraphobia. Since then, a considerable number of retrospective, as well as longitudinal, studies have been published ( 5 – 7 , 10 – 13 ), indicating that the volume of evidence on this topic has rapidly increased. To our knowledge, however, no systematic review or meta-analysis addressing the outcomes of childhood separation anxiety disorder has been published. Consequently, a meta-analysis examining the outcomes of childhood separation anxiety disorder is of highest clinical and conceptual relevance.

To test the relationship between childhood separation anxiety disorder and subsequent mental disorders in adolescence and adulthood, we performed meta-analyses of epidemiological studies investigating the association between childhood separation anxiety disorder and panic disorder, anxiety disorders in general, major depressive disorder, or substance use disorders. Selected outcomes were chosen because of their theoretical relation to separation anxiety disorder ( 8 ), as well as a sufficient number of empirical studies investigating the associations. In addition, possible moderators were identified by examining subgroup analyses.

Search Strategy and Inclusion Criteria

We performed searches in PubMed, PsycINFO, and Embase of studies published through December 31, 2011, using the keyword “separation anxiety.” In addition, the references of all included articles were reviewed, and researchers in the field were contacted and asked if they were aware of additional relevant publications. Eligibility judgments were performed independently by two reviewers (J.K. and C.L.). Inconsistencies were resolved in consensus meetings and confirmed with a third reviewer (M.C.P.) when necessary. We included peer-reviewed published articles comparing children with separation anxiety disorder with children without separation anxiety disorder or with other mental disorders with regard to future mental disorders in adolescence and adulthood. Case-control, prospective, and retrospective cohort studies that were in either English or German were included. Only studies using explicit, reliable, and reproducible diagnostic criteria for separation anxiety disorder and outcome variables, which were based on DSM-III, DSM-III-R, DSM-IV, or ICD-10, were included. Outcomes had to be reported as odds ratios or in other ways that allowed for their calculation. Prospective studies with a follow-up period less than 2 years were excluded, as were case reports, comments, letters, and reviews. Any disagreements were discussed, and a consensus was reached. With these criteria, 25 studies were identified and included in our analysis ( 5 – 7 , 10 , 11 , 13 – 32 ) ( Table 1 ).

a OCD=obsessive-compulsive disorder; STROBE=Strengthening the Reporting of Observational Studies in Epidemiology.

b The data refer to the Biederman et al. study on childhood antecedents to panic disorder ( 13 ).

c The data refer to the Biederman et al. study on patterns of comorbidity in panic disorder and major depression ( 17 ).

Quality Assessment

Two of the reviewers (M.C.P. and C.L.) independently evaluated the methodological quality of the studies using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement ( 33 ). Items 11, 12c, 16b, 16c, 17, and 22 of the STROBE were disregarded because they were either not applicable to the studies under investigation or did not appropriately differentiate between studies of low and high quality. For items 7 and 16a, the studies were rated by assigning 0, 0.5, or 1 point as appropriate. For the remaining items, the studies were rated by assigning 0 or 1 point. Disagreements regarding data extraction or quality of the studies were resolved by consensus among reviewers.

Data Extraction and Analysis

Data were extracted independently by two of the reviewers (J.K. and M.C.P.). Inconsistencies were resolved in consensus meetings. Extracted data were converted to odds ratio effect sizes and 95% confidence intervals reflecting the probability of unfavorable outcomes, with odds ratios above 1 reflecting a greater likelihood of future psychopathology in individuals with a history of childhood separation anxiety disorder compared with those without. Data management, log-transformation of effect sizes, and calculation of the pooled mean effect sizes were performed using Comprehensive Meta-Analysis, version 2.0 ( www.meta-analysis.com ). Since considerable heterogeneity was expected, all analyses were performed with a random-effects model. We used this model because it is preferable to fixed-effects models, particularly with relatively small numbers of studies with expected high heterogeneity ( 34 ). Log-transformed odds ratio estimates were pooled using the inverse of their variance as weights ( 35 ).

The majority of cohort studies prospectively investigated separation anxiety disorder samples compared with non-separation anxiety disorder samples, which included individuals with no history of childhood separation anxiety disorder but with other potential present or lifetime diagnoses. Case-control studies retrospectively investigated the clinical population under investigation (i.e., individuals with panic disorder, major depressive disorder, other anxiety disorders, or substance use disorders) compared with either a clinical comparison group including subjects with a variety of current disorders other than the outcome variable under investigation (these disorders are listed in Table 1 ) or a nonclinical comparison group (i.e., healthy or nonpsychiatric comparison subjects), with regard to a history of separation anxiety disorder. Two studies included data for both nonclinical and clinical comparison subjects ( 7 , 21 ). To avoid the problem of correlated data, the odds ratios for these studies were calculated for a pooled comparison group and not included in the subgroup analysis differentiating between the comparison groups. One study included two separate samples ( 15 ), and the data were treated as belonging to separate cohorts.

To assess heterogeneity between studies, we used the Q statistic. A statistically significant Q indicates a heterogeneous distribution of odds ratios between studies, meaning that systematic differences, possibly influencing the results, are present ( 36 ). In addition, the degree of inconsistency was quantified by the I 2 statistic, which measures the percentage of variation across studies that is a result of heterogeneity rather than chance ( 37 ). A value of 0% means no heterogeneity, and higher values indicate greater heterogeneity. Generally, heterogeneity is considered low at an I 2 value of 25%, moderate at a value of 50%, and high at a value of 75% ( 37 ).

Additional sensitivity analyses explored the effects of various possible sources of artifact or bias on the results. First, we assessed the presence of publication bias visually by funnel plot ( 38 ) and formally by its direct statistical analogues, the Begg adjusted-rank correlation test ( 39 ) and the fail-safe N method ( 40 ). Sensitivity to the estimate of publication bias was assessed by the trim-and-fill method ( 41 ). Second, we performed subgroup analyses to test for significant differences between odds ratios in different categories of studies. Of greatest interest were differences with regard to comparison groups, study type, study population, diagnostic criteria (i.e., DSM-III, DSM-IV), differential symptom assessments (i.e., participant report, parental report, or both), data collection methods (i.e., questionnaire, structured interview), sociodemographic characteristics (i.e., age, sex, family background, familial stress, parental psychopathology), and severity of and age at onset of separation anxiety disorder. Furthermore, we assessed the impact of study quality on the meta-analysis results. To evaluate the statistical stability of results, studies rated as “poor” in quality (i.e., STROBE values <10) were removed in a separate analysis, and the pooled odds ratio, with 95% confidence interval, was recalculated and compared with the original results. Differences between odds ratios were calculated using a z test ( 42 ).

Study Selection

The study selection procedure is summarized in Figure 1 .

Association Between Separation Anxiety Disorder and Future Mental Disorders

In investigating the association between separation anxiety disorder and panic disorder, we first assessed whether there was a difference between the independent studies investigating the association between separation anxiety disorder and panic disorder and the association between separation anxiety disorder and panic disorder with agoraphobia. We found that this was not the case (odds ratio=3.59; 95% confidence interval [CI]=2.92–4.42, compared with odds ratio=4.19; 95% CI=2.15–8.15; p=0.66). We therefore combined the two panic disorder groups.

Twenty-five studies were included in the meta-analysis ( Table 1 ). Meta-analysis revealed that children with a history of separation anxiety disorder were more likely than those without to develop panic disorder later on (odds ratio=3.45, 95% CI=2.37–5.03) ( Figure 2 ). We identified significant heterogeneity across studies (Q=79.01, df=23, p<0.001; I 2 =70.89, tau 2 =0.50). There was no evident publication bias in a funnel plot. The Begg’s test result was not statistically significant, and the fail-safe N indicated that 782 unpublished null studies would be needed to remove the significance from the findings. The trim-and-fill method did not lead to any adjustment of the odds ratio.

a The red diamonds indicate the combined effect sizes for studies with clinical, nonclinical, and non-separation anxiety disorder comparison groups, as well as the overall effect size of the meta-analysis (top to bottom). An asterisk indicates that the study included two separate separation anxiety disorder samples, and the data were treated as belonging to separate cohorts.

Five studies were included to test the association between separation anxiety disorder and any anxiety disorder ( Table 1 ). Because of the problem of adult anxiety comorbidity in case-control studies, it was not possible to combine various anxiety disorder groups for those studies. We therefore included only studies that specifically included any anxiety disorder as an outcome. Two of the five studies included odds ratios for any anxiety disorder other than panic disorder ( 5 , 7 ), while three studies included odds ratios for any anxiety disorder including panic disorder ( 6 , 21 , 29 ). However, the odds ratios of the former and the latter studies did not differ from each other. All five studies exhibited moderate heterogeneity (Q=7.55, df=4, p=0.11; I 2 =47.04, tau 2 =0.11). Results suggested that a childhood diagnosis of separation anxiety disorder significantly increases the risk of any anxiety disorder (odds ratio=2.19; 95% CI=1.40–3.42). Because of the low number of studies, no sensitivity analyses or publication bias was assessed.

Fourteen studies were included to test the association between separation anxiety disorder and major depressive disorder ( Table 1 , Figure 3 ). We identified significant moderate heterogeneity across studies (Q=31.71, df=13, p=0.003; I 2 =59.01, tau 2 =0.14). Results suggested that a childhood diagnosis of separation anxiety disorder significantly increases the risk for the development of major depressive disorder (odds ratio=1.36; 95% CI=1.01–1.83). However, there was evidence of some possible publication bias in a funnel plot. The Begg’s test result was not significant, and the fail-safe N indicated that 26 unpublished null studies would be needed to remove the significance from the findings. The trim-and-fill method led to a nonsignificant corrected odds ratio of 1.06 (95% CI=0.78–1.45).

a The red diamonds indicate the combined effect sizes for studies with clinical, nonclinical, and non-separation anxiety disorder comparison groups, as well as the overall effect size of the meta-analysis (top to bottom).

Five studies were included to test the association between separation anxiety disorder and substance use disorders ( Table 1 ). These studies revealed good between-study homogeneity (Q=5.84, df=4, p=0.21; I 2 =31.41, tau 2 =0.09). Results suggested that a childhood diagnosis of separation anxiety disorder does not increase the risk of substance use disorders (odds ratio=1.27; 95% CI=0.80–2.03). Because of the low number of studies, no sensitivity analyses or publication bias was assessed.

Sensitivity Analyses and Moderator Variables

Because of the small number of studies investigating substance use disorders and any anxiety disorder as outcomes, sensitivity analyses were performed only for the association between separation anxiety disorder, panic disorder, and major depressive disorder ( Table 2 ). Studies with nonclinical comparison subjects revealed that individuals with separation anxiety disorder were more likely to develop panic disorder (p<0.001) and major depression (p=0.02) than individuals in studies with clinical comparison subjects. Furthermore, population studies reported a significantly higher association with panic disorder (p=0.03) and major depression (p<0.01) than clinical studies. The nonclinical comparison subjects were similarly distributed between the two sample types.

a The data represent the variance between studies as a proportion of the total variance; heterogeneity was tested using the I 2 statistic (low heterogeneity=25%; moderate heterogeneity=50%; high heterogeneity=75%). The p values refer to significance of the Q statistic (the I 2 statistic does not include a test of significance).

b Heterogeneity was tested using the tau 2 statistic, which estimates the between-study variance.

c The data represent the Z value of the test of interaction between different categories of studies (Altman and Bland [ 42 ]).

* p≤0.05. ** p≤0.01. *** p≤0.001.

No differences were found between the different types of studies (i.e., case-control, prospective, and retrospective cohort studies), diagnostic criteria, data collection methods, and differential symptom assessments. However, only five studies included both parents and participants as informants, while the remaining studies relied solely on participants. To evaluate the statistical stability of the results, the two studies with low STROBE scores ( 15 , 31 ) were removed. The removal of these studies decreased the overall effect on the separation anxiety disorder-panic disorder link by only 6% and the link to major depression by 1.5%.

No meta-analyses were performed for the moderator variables described below because of the low number of studies including these moderator variables. However, we summarize the study results here because of their potential relevance to future psychopathology.

Aschenbrand et al. ( 5 ) observed no significant differences between individuals who were successfully treated as children and those who were not successfully treated as children with regard to the frequency of clinical panic disorder at long-term follow-up evaluation. No other studies compared these two groups.

Only two studies ( 15 , 16 ) explicitly investigated the link between separation anxiety disorder and panic disorder separately for male and female subjects, yielding conflicting results, and only three studies ( 6 , 7 , 27 ) included sex as a covariable.

Four studies provided information about the age at onset of separation anxiety disorder ( 6 , 7 , 26 , 29 ), but none examined the influence of this variable on the development of future psychopathology. One study examined parental psychopathology and found that the familial risk of panic disorder was similar for patients both with and without separation anxiety disorder ( 16 ). Only three studies ( 7 , 20 , 27 ) included comorbidities during childhood as a covariable in the analyses. None of the studies clearly controlled for comorbid adult anxiety disorders or investigate the influence of separation anxiety disorder severity level.

Our meta-analysis addressed the possible development of panic disorder, any anxiety disorder, major depressive disorder, and substance use disorders in children with separation anxiety disorder. The results indicate that a childhood diagnosis of separation anxiety disorder significantly increases the risk of panic disorder but also of other anxiety disorders, as indicated by the association with any anxiety disorder as well as the nonsignificant association with panic disorder when compared with other anxiety disorders. After adjusting for possible publication bias, no association with major depression or substance use disorders was found.

There was evidence of both clinical and statistical heterogeneity in the included studies. Studies using nonclinical comparison subjects as reference groups often obtained significantly higher overall odds ratios than studies using clinical comparison and non-separation anxiety disorder reference groups and demonstrated that children with separation anxiety disorder have almost six times the odds of developing panic disorder than children without separation anxiety disorder. However, the nonsignificant association of separation anxiety disorder with panic disorder in studies with clinical comparison subjects with various anxiety disorders indicates that children with separation anxiety disorder do not have a greater risk of developing panic disorder than of developing other anxiety disorders. Even in studies using comparable reference groups, odds ratios were substantially influenced by the amount of separation anxiety symptoms in the reference group. For example, the odds ratios for lifetime panic disorder in one study ( 6 ) was 51.2 when compared with a reference group with no separation anxiety symptoms, compared with an odds ratio of 28.2 when a subthreshold reference group with symptoms was used (T. Brückl, personal communication, March 2012). In summary, the lack of a clear standard with regard to comparison groups makes it difficult to compare the effects of other possible moderators and their possible interactions. The use of a standardized comparison group would allow for more accurate statements regarding the described confounding effects of heterogeneity.

Two interesting nonfindings deserve emphasis. The association between separation anxiety disorder and major depressive disorder was nonsignificant after correcting for publication bias. Many reasons for publication bias and ways of dealing with it have been identified ( 43 , 44 ). The trim-and-fill method imputes the number and most probable results of unpublished experiments to calculate an estimate of what the effect size would be in the absence of publication bias ( 41 ). However, even without eliminating publication bias, the association was borderline significant. In summary, the data suggest that the association with major depression is weak, but more studies, especially longitudinal studies, are necessary to clarify the issue. The nonfinding of substance use disorders might be due to the samples investigated. Studies differentiating between men and women might uncover possible sex-specific courses and outcomes, such as substance use disorders, which are commonly found in men but not women. Although unexpected, the nonsignificant effect owing to study type and informant type cannot be explained by the possible confounding effect of a strong coincidence with either nonclinical or clinical comparison subjects.

This study has several limitations. First, we included articles published in English and German but not in other languages. Second, methodological differences between the studies limit the generalizability of the results. Similarly, because of the low number of outcome studies investigating anxiety in general and substance use disorders, these results should be considered preliminary and require further investigation. Third, lifetime diagnoses based on retrospective report may be subject to recall bias ( 45 ), although we found no difference between retrospective and prospective studies. It may be that separation anxiety is less vulnerable to recall bias because of the prominent and observable nature of the disorder and the impairment it causes in daily life activities. Fourth, despite the fact that our data suggest an association between separation anxiety disorder and future pathology, they do not allow for comments about causality. Although it is possible that separation anxiety disorder is a causal agent for subsequent psychopathology, it is also possible that childhood separation anxiety disorder and adult anxiety and panic pathology may be caused by a common underlying vulnerability. Lewinsohn et al. ( 7 ) proposed that if the latter is true, then it might also be true that separation anxiety disorder is a marker for severity of the underlying vulnerability. The use of a quantitative measure of separation anxiety disorder severity, such as the Separation Anxiety Symptom Inventory ( 46 ), might help in shedding light on the issue. Finally, because only few studies addressed the issue of childhood or adult anxiety comorbidity, our results do not address the specificity of the association between separation anxiety disorder and the outcomes in adulthood. It remains unclear whether the individual studies were adequately powered to detect a difference between panic disorder and other anxiety disorders. This problem posed by a naturalistic study design and the consequent naturalistic problem of positive publication cannot be rectified by statistical adjustment procedures, such as the trim-and-fill method. It is further plausible that links between childhood separation anxiety disorder and future psychopathology are attributable, completely or partially, to the presence of the comorbid condition (e.g., adult separation anxiety disorder) ( 11 ). Studies specifically comparing children with other psychopathologies and healthy children with regard to future psychopathology and controlling for adult comorbidity would be necessary to correctly estimate the specific and nonspecific effect of separation anxiety disorder and whether it is a specific risk factor for panic disorder or a general risk factor for future anxiety disorders.

Despite these limitations, we found clear indications for an association between childhood separation anxiety disorder and future anxiety and panic disorders. These results support a developmental psychopathology conceptualization of anxiety disorders, a perspective that is expected to be strengthened in DSM-5 ( 47 ). Preliminary evidence suggests a developmental pathway that may start with exaggerated stranger anxiety in infancy ( 48 ). Understanding stranger anxiety as an age-dependent developmental task may provide new insight to our understanding of the etiology of separation anxiety disorder. Developmental cascades and developmental tasks are integrally related ( 49 ). Thus, the effects of maladaptive functioning in a domain early in development can become more pervasive or diffuse as that function affects the quality of the child’s experience, amplifying its effect and ultimately becoming entrenched as a more significant disorder ( 50 ). Children suffering from separation anxiety disorder may be hindered early in life in developing skills to help cope with anxiety and strong emotions, both being important for healthy development.

The pathophysiological processes behind the developmental pathway in separation anxiety disorder remain unclear. However, the early onset of separation anxiety disorder suggests that genetic factors and shared environmental factors may be of particular importance ( 51 ). It can be assumed that shared environmental influences in the family decrease with age, having their greatest effects during childhood ( 52 ). Consistent with this assumption, twin studies have revealed no or only small shared environmental influences on anxiety disorders in adulthood ( 53 – 55 ) but a significant influence in children and adolescents ( 52 , 56 , 57 ), accounting for approximately 14%–21% of the variance ( 58 , 59 ). Current psychophysiological studies postulating a unique genetic association between separation anxiety disorder and the development of adult-onset panic attacks have shown that children with separation anxiety disorder exhibit manifest CO 2 sensitivity ( 60 – 62 ). The study of further pathological mechanisms shared by both separation anxiety disorder and panic disorder patients is needed, such as the role of attachment ( 63 ). With regard to clinical care, the meta-analytical evidence of an association with future anxiety and panic disorder calls attention to the importance recognizing and treating separation anxiety disorder as early as possible. Treatment studies have shown that separation anxiety disorder can be successfully treated with disorder-specific parent-child cognitive-behavioral therapy ( 64 ).

The authors report no financial relationships with commercial interests.

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Ten years of researches on generalized anxiety disorder (GAD): a scientometric review

• Published: 11 April 2024

Cite this article

• Ying Zhou 1 , 2 ,
• Yulin Luo 2 ,
• Na Zhang 3 &
• Shen Liu   ORCID: orcid.org/0000-0002-6900-8831 2  

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Generalized anxiety disorders (GAD) is a chronic anxiety disorder characterized by autonomic excitability and hypervigilance. However, there was currently a lack of a quantitative synthesis of this time-varying science, as well as a measure of researchers’ networks and scientific productivity. Searching from the Web of Science Core Collection, PubMed, and Scopus on January 31st, 2024. The scientometric analysis was realized and the clinical research of GAD in recent ten years was explored. 9703 studies published from 2014 to 2023 were included, which aggregated into a well-structured network with credible clustering. It was worth studying the recent trend of productivity. Eleven clusters were identified by the co-citation reference network. The network structure was reasonable ( Q  = 0.5996) and the clustering reliability was high ( S  = 0.8378). The main trend of research is ‘’china’’, ‘’epidemic’’. These results can provide reference for the future development of funding agencies and research groups.

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Data availability

The datasets generated and analyzed during the current study are not publicly available. The datasets are available from the corresponding author on reasonable request when the aim is to verify the published results.

Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.

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Acknowledgements

This study was supported by the Outstanding Youth Program of Philosophy and Social Sciences in Anhui Province (2022AH030089) and the Starting Fund for Scientific Research of High-Level Talents at Anhui Agricultural University (rc432206).

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Zhou, Y., Luo, Y., Zhang, N. et al. Ten years of researches on generalized anxiety disorder (GAD): a scientometric review. Curr Psychol (2024). https://doi.org/10.1007/s12144-024-05872-2

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The Biology of Anxiety

Reviewed by Psychology Today Staff

Anxiety is both a mental and physical state of negative expectation—mentally characterized by increased arousal and negative expectancy tortured into worry, and physically by activation of multiple body systems—all to facilitate coping with an unknown or adverse situation.

It is a state of defense presided over by nerve circuits of fear and activated by misperception or overestimation of threat from the environment, from the inner world of the body, or from the inner world of thought. Anxiety is a normal response to threat, and the discomfort it creates is meant to capture attention and stimulate a protective response. But too often, the anxiety is excessive, or sustained, or inappropriate to what set it off, and it interferes with every-day functioning—or sets in motion maladaptive behaviors, from avoidance of threat-generating situations to substance use, to avoid the discomfort of anxiety.

A number of neural structures play a role in anxiety, but the one that gives it its strong emotional color is the amygdala. The rational, thinking prefrontal cortex is responsible for interpreting the nature of the threat and orchestrating a behavioral response. Other brain areas also respond to the threat, and the signals they generate turn on the stress response, activating all the body systems for fight or flight..

Researchers believe that anybody can experience a bout of debilitating anxiety. But some people seem to be dispositionally inclined to anxiety: Their defense systems—possibly tuned by genes or temperament, possibly by early experience, possibly by over- or underactivity of some area of the brain—are poised to over-interpret neutral situations as threatening or to overreact to threatening situations.

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• What happens in the brain with anxiety?
• What areas of the brain are involved in anxiety?
• Why do I feel anxiety in my body?
• How do anxiety and fear differ in the brain?
• How do anxiety and depression differ in the brain?
• How does nerve cell communication go awry in anxiety?
• Why do I feel restless and unable to concentrate?
• Why can't I sleep?
• What do brain scans look at in anxiety?
• What do drugs target to relieve anxiety?
• What are the effects of anxiety on the brain?
• What happens in the brain with panic attacks?

Once the amygdala flags incoming information as a threat—or, due to hyperreactivity, jumps to that conclusion even in the absence of threat—it sends out an alarm, notifying many other areas of the brain to prepare for defensive action. It acts as if your life may be at stake. The hypothalamus relays the signal neurally and hormonally, setting off the stress response. Heart rate increases. Blood pressure rises. Breathing quickens. Areas in the brainstem switch on, pitching you into a state of high alertness and vigilance. The hippocampus, home of memory, draws on past experience to try to put the nature of the threat into context. The prefrontal cortex, which receives all the information to create a coherent interpretation of events and to orchestrate an appropriate behavioral response, can dampen or amplify the sense of threat and degree of distress. In the anxious brain — whether through overexcitability of the stress response system, the activity of various neurochemicals, impairments in nerve circuitry, or inactivation of specific cell populations in the prefrontal cortex—the amygdala essentially overpowers the prefrontal cortex.

Anxiety starts when the central emotional processor known as the amygdala—or the so-called “extended amygdala,” which encompasses the bed nucleus stria terminalis (BNST)—interprets incoming stimuli from the inner or outer world as a threat. A distress signal is sent out to many other parts of the brain, including the hypothalamus, which in turn relays the signal to the rest of the body by switching on the sympathetic nervous system. The release of epinephrine (adrenaline) from the body’s adrenal glands jolts the brain into alertness, sharpening senses and demanding hypervigilance of the environment. The amygdala also communicates with the hippocampus, repository of memory, which can put the threat signal into comforting context—or not.

Normally, through their many interconnections, the prefrontal cortex, seat of executive functioning, exerts control over the emotional output of the amygdala. But the negative emotional signals emanating from the activated amygdala, amplified by the excitatory neurotransmitter glutamate, disrupt cognitive functioning, including decision-making, and keep the prefrontal cortex from switching to other matters. Anxiety short-circuits the decision-making process by literally suppressing the normal activity of specific populations of neurons in the prefrontal cortex.

Regardless how real or imagined a threat is, anxiety is a response to perception of danger. It is both psychological and physical . The brain’s amygdala makes the determination of threat and signals the hypothalamus, a central command center, which broadcasts the signal through the autonomic nervous system and sets off a cascade of hormones, including adrenaline. Body and mind prepare as if your life were at stake.

Before you even have a chance to ponder the nature of the danger—before the hippocampus, seat of memory, has a change to put the threat in the context of past experience—you are jolted into alertness and begin searching everywhere for signs of trouble; you can’t concentrate—and you can’t sleep. Your body prepares you for rapid action. Your heart begins pumping blood fast. As your heart rate goes up, so does your blood pressure and your breathing rate. You feel muscular tension, even twitchiness. You may feel a headache or stomachache. Many people experiencing anxiety seek treatment for the bodily symptoms, believing they must be due to physical causes, without the true source of the problem being discovered.

All animals experience fear. But the evidence suggests that only humans experience anxiety, which has been called “the price we pay for an ability to imagine the future.” Fear is a response to a direct threat. Anxiety is a response to a possible negative outcome ahead. But both fear and anxiety utilize much of the same neural circuitry, with the amygdala flagging incoming stimuli as threatening and turning on defense systems of body and brain—vigilance, muscular tension, rapidly beating heart. The amygdala overpowers the rational part of the brain, the prefrontal cortex, that normally interprets and regulates emotional experience and directs a behavioral response. Much of that brain machinery overlaps in fear and anxiety.

But the unique element in anxiety is the capacity to imagine some negative future outcome. Anxiety can be considered a condition of suffering from imagination . Imagination is a kind of mental tinkering with various kinds of information stored in different parts of the brain. At the very least it involves the capacity to manipulate mental imagery, which centers in the visual cortex. Whether positive or worrisomely negative, imagination is a very complex capability that is still largely uncharted territory, including its role in anxiety.

The symptoms of anxiety and depression overlap in many ways—both conditions create irritability, insomnia, and difficulty concentrating, for example. Researchers know that some of the same brain centers are involved in both conditions—such as the amygdala, commonly called the fear center but more appropriately thought of as an emotion center, and the hippocampus, seat of memory. But scientists are still actively disentangling the relative contributions of the amygdala and the hippocampus in the two disorders, and the relationship between the two areas is now the focus of much attention.

Normally, the hippocampus is an important way station in the interpretation of all incoming information. From its memory bank, the hippocampus puts stimuli in context so the brain can figure out how to handle situations. Depression impairs the functioning of the hippocampus and actually shrinks its size. Anxiety, on the other hand, enlarges the hippocampus. It turns on a small group of cells researchers now refer to as “anxiety cells”—for example, in studies of animals, the cells fire only when the animals are in places that are innately frightening to them.

Through messaging to other parts of the brain, the firing of the anxiety cells then turns on many of the behaviors associated with anxiety, including avoidance of any situations that bring on the discomfort. The anxiety cells of the hippocampus also signal the hypothalamus, a switching center that communicates with the body; they trigger the hypothalamus to produce many of the symptoms you experience in anxiety— increased heart rate and breathing, muscular tension. The brain signals in anxiety also command visual centers to heighten visual attention. The resulting hypervigilance represents one of the many ways the brain overestimates the possibility of threat, the hallmark of anxiety.

Researchers and clinicians once focused on the role of neurotransmitters in anxiety and its close cousin depression. Over the past 25 years, however, it has become clear that neurotransmitters are only one part of a much larger story of how nerve cells function in circuits to relay messages from one part of the brain to another. In fact, many experts see anxiety as a nerve circuit disorder, marked by a power disruption in the brain’s wiring, affecting communication between one area of the brain and another.

The nerve cell connections between the amygdala and the prefrontal cortex (PFC) are critical in anxiety. Anxiety results when alarm signals of possible danger originating in the amygdala disable the PFC so that it can not ignore or in any way regulate the signals. In fact, the PFC sends out signals that intensify amygdala activity, and the PFC winds up collaborating in the loss of its own control over the amygdala. The hyperactive amygdala also bullies the visual center of the brain to maintain constant vigilance, ever on the lookout for threats, allowing the misinterpretation of benign stimuli as dangerous ones.

Restlessness is anxiety’s badge of readiness for protective action. Anxiety is by definition a brain state of unease , and a heady cocktail of hormones unleashed by the perception of threat works diligently to maintain a state of preparedness for action. Alarm signals of possible danger sent from a hyperactive amygdala prompt the release of adrenaline to put many systems on high alert for immediate action. Visual systems go on permanent watch, specifically searching for signs of trouble and biased to notice them even when they don’t exist. Every muscle of the body is twitching with anticipation that some bad outcome lies just ahead, twitching with the possibility that fight or flight might be necessary. Restlessness is part of the price of protection for an organism that has the gift of imagining the future.

Anxiety and insomnia are exquisitely uncomfortable but longstanding bedfellows; studies show that anxiety brings on insomnia in the vast majority of cases. Anxiety sets up a vicious cycle with sleep. Anxiety is a state of neural and general physiologic arousal. The hypervigilance that is a hallmark of anxiety keeps the brain in a constant state of unease, on high alert for threat, interfering with the ability to rest. The resulting loss of sleep creates fatigue, irritability, and inability to concentrate during waking hours, eroding ability to manage anxiety or attend to any of the matters that serve as the source of concern or threat. Researchers find that brain activity after periods of sleep deprivation mirrors brain activity indicative of anxiety disorders. The emotion-generating amygdala is especially active after sleep deprivation , while brain regions that normally modulate emotional experience are muted. In fact, sleep deprivation can cause an anxiety disorder. Sleep disturbance is a diagnostic symptom of anxiety disorders.

Some types of brain imaging, such as CT scans and magnetic resonance imaging (MRI), take static pictures of the brain to determine whether any specific structures are larger or smaller than normal in anxious patients. Positron emission tomography (PET) scans and functional magnetic resonance imaging (fMRI) look at the brain in action, to see whether and where there are problems in the way the brain processes specific types of information . They delineate the circuitry of anxiety, indicating which parts of the brain play a role in the disorder.

In fMRI studies, normal controls and anxious patents are typically given some task to perform in the scanner. For example, subjects may be asked to look at a series of pictures, some of them with emotionally disturbing content, to see how the brain handles negative and, particularly, threatening stimuli. The brain scanners measure blood flow or metabolic activity, based on the concentration of tagged agents earlier injected into the bloodstream. Comparison of hot spots and dead spots of activity between controls and anxious patients highlights areas of the brain that malfunction in response to the stimuli. Such studies consistently show heightened activity in the amygdala, which flags emotional information as alarming, and underperformance in areas related to shifting attention away from troublesome thoughts and controlling emotional response.

There is no one drug target in anxiety—at least not yet. The first line of pharmacological defense against anxiety disorders (except panicCK) is the SSRIs, or selective serotonin reuptake inhibitors, such as citalopram (Celexa) and fluoxetine (Prozac)., and their first cousins the SNRIs, selective noradrenaline and serotonin reuptake inhibitors, such as duloxetine (Cymbalta) and venlafaxine (Effexor). They have been widely studied, and most clinicians find that, as in depression, such drugs have limited efficacy and limited duration of effects—largely because they reflect the limited understanding of anxiety and its twin disorder, depression, that existed 30-plus years ago, when they were developed.

Both groups of drugs are aimed at boosting concentrations of one neurotransmitter or another, in the belief that anxiety (and depression) results from a chemical deficit in the brain. The drugs block the reuptake of serotonin or noradrenaline at synapses, thus increasing levels of the neurotransmitters. Huge gains in the study of the brain over the same time show that anxiety is an enormously complex disorder, involving many parts of the brain forming a circuit dealing with signals of threat. Researchers still have not nailed down exactly which parts of the brain play a role in the disorder, under what conditions, and exactly what that role is. Anxiety is particularly elusive because the stimuli to worry are so idiosyncratic and memory-specific.

Another class of drugs often used to treat anxiety is the bendodiazepines, including Valium, Xanax, and Klonopin. They curb anxiety by exerting a generally sedating effect on the brain, and they, too, act by targeting neurotransmitters, specifically acting on brain receptors for GABA, the brain’s inhibitory neurotransmitter, to increase its levels.. More GABA available slows down the brain and tamps down all nervous system activity. Benzodiazepines have been used since the 1950s as tranquilizers and sedatives to facilitate sleep, and all bear a warning label that they can create dependency.

Anxiety is the number one mental health problem in the world. There is widespread hope that by targeting one or more brain centers involved in neural circuits of anxiety, science will find a drug that is effective in curbing the condition.

Generalized anxiety disorder can have negative effects on many brain structures and functions including cognition, changing the way we think . For one, it biases the brain toward noticing the negative, predisposing to depression as well. The brain becomes hyperreactive to threats, seeing neutral events as threatening and responding with worry—rumination about possible bad outcomes.

The three main brain centers in the circuitry of anxiety—the amygdala, the hippocampus, and the prefrontal cortex (PFC)—are all subject to lasting shifts in structure and function as a result of the disorder. Most notably, the amygdala grows in size and output, biasing it to issue false alarms of danger. The PFC shrinks in size and activity, weakening its ability to make sense of emotional experience and direct an appropriate response. The impairment of cognitive function is not limited to processing emotional information but extends to all problem-solving. For its part, the hippocampus preferentially holds on to threat-related memories. Further, the corrosive effects of anxiety on the PFC and hippocampus set the already compromised brain up for dementia, such as Alzheimer’s disease.

Panic attacks are dramatic bursts of anxiety that feel acutely life-threatening but are not. The body sensations of anxiety—pounding heart, racing pulse, the feeling of difficulty taking in air—become so intense so quickly you feel as if you are having a heart attack and are about to die . That interpretation is mistaken, but it triggers even more anxiety, intensifying the panic. Experts find that something goes wrong in the normal brain circuits of communication between the emotional output center of the amygdala and the cognitive processing and regulation center of the prefrontal cortex (PFC). Overwhelmed by signals from the amygdala, the prefrontal cortex does not realize that the threat is not real. People differ in the degree to which they are aware of their inner workings of their body (interoception), and there’s some evidence that those who are subject to panic attacks are especially highly attuned to body sensations.

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Biological Explanations of Generalized Anxiety Disorder: Effects on Beliefs About Prognosis and Responsibility

• Matthew S. Lebowitz , M.S., M.Phil. ,
• John J. Pyun , B.S. , and
• Woo-kyoung Ahn , Ph.D.

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Biological explanations of psychopathology can reduce the extent to which people with mental disorders are blamed for their symptoms but can also yield prognostic pessimism—the belief that psychiatric conditions are relatively immutable. However, few studies have examined whether these effects occur among persons who actually have psychiatric symptoms. This study sought to address this question.

Adults living in the United States (N=351) were recruited online in January and February 2012 and assessed for symptoms of generalized anxiety disorder. The participants were randomly assigned to two groups: a biological condition, in which participants (N=176) were provided a description of generalized anxiety disorder and a biological explanation of the etiology of the disorder, and a control condition, in which participants (N=175) were provided the same description without any explanation of etiology. Dependent measures of treatability, duration of symptoms, and responsibility for symptoms were used to gauge beliefs regarding the prognosis and personal responsibility of a typical person with generalized anxiety disorder.

Among participants with and without symptoms of generalized anxiety disorder, the biological condition was associated with decreased ascriptions of personal responsibility for anxiety (p=.02) and expectations of increased duration of symptoms of generalized anxiety disorder (p=.01).

Conclusions

This finding has important social and clinical implications, especially because biological conceptualizations of psychopathology are increasingly prevalent. By causing prognostic pessimism about generalized anxiety disorder, including among those with symptoms of the disorder, biological explanations could negatively affect treatment seeking and outcomes. Efforts to dispel the link between biological explanations and prognostic pessimism are needed.

Generalized anxiety disorder, a common mental disorder ( 1 ), is increasingly explained in terms of neurobiology and genetics ( 2 – 5 ). Members of the public have also become more likely to believe in biological explanations for mental disorders, including neurochemical imbalances and genetic abnormalities ( 6 ). This conceptual shift was once seen as a potential destigmatizing force, dispelling perceptions that individuals with mental disorders are responsible for their own problems ( 7 – 9 ). Indeed, empirical evidence links biological conceptualizations of psychopathology with reduced blame ( 10 – 12 ).

However, some research has linked biological construals of mental illness to more, not less, negative attitudes toward people with psychiatric illnesses ( 7 – 9 ), including pessimism about the prognoses of mental disorders ( 13 – 16 ). This prognostic pessimism reflects “neuroessentialism” and “genetic essentialism”—the inaccurate beliefs that mental disorders have fundamental, immutable essences (in the brain and genes, respectively) ( 8 , 9 ). This study attempted to address several unanswered questions concerning this phenomenon.

First, most research has looked at prognostic beliefs among the general public rather than among persons with symptoms of mental disorders. However, information about prognostic pessimism among symptomatic individuals would be clinically important, given that outcome expectancies are a key determinant of actual prognosis and responsiveness to treatment ( 17 , 18 ). In fact, patients who expect positive outcomes are more likely to seek treatment or engage with it fully ( 19 , 20 ). Furthermore, people with psychopathology may be especially likely to hold biological beliefs about their disorders ( 21 ), given that they may be biologically related to persons with the same disorder or prefer explanations that deflect personal responsibility. Thus it is important to understand how individuals are affected by biological explanations of disorders with which they have personal experience.

A few studies examined the effects of biological explanations of mental disorders among individuals with psychiatric symptoms, but they had limitations. In one study, endorsement of biological causation of depression was linked to prognostic pessimism among symptomatic individuals ( 22 ), but this research was correlational, precluding conclusions about whether the biological beliefs actually caused the prognostic pessimism. In one experimental study ( 16 ), patients showed more prognostic pessimism when told that an individual’s panic disorder was caused by biological rather than psychological factors, but panic disorder was not the diagnosis of anyone in the sample. Thus it remains unknown whether biological explanations might affect people’s prognostic expectations regarding their own mental health. Perhaps direct experience leads individuals to form strong, concrete beliefs about the causes or prognoses of their own mental disorders, which could be difficult to change, for example, by using biological explanations. Thus biological explanations of mental illness might be less likely to engender prognostic pessimism or otherwise alter beliefs among individuals with personal experience of mental disorders compared with persons without such experience.

In addition, despite their high prevalence among adults ( 1 ), anxiety disorders have received relatively little attention in studies of etiological beliefs and their consequences. Most research about beliefs about mental illness have examined mental illnesses generally or depression, schizophrenia, or substance dependence ( 6 , 7 , 23 ). However, not all mental disorders are subject to the same attitudes and beliefs. For example, although most research has found that biological explanations do not reduce negative attitudes toward psychopathology, some research suggests that they may reduce stigmatization of some disorders ( 24 ). To our knowledge, this study represents the first of its type to focus on generalized anxiety disorder. Because this disorder is characterized by excessive worry about the future ( 1 ), its sufferers may be particularly vulnerable to concerns about their own health, including mental health. Thus, by contributing to prognostic pessimism, biological explanations of generalized anxiety disorder could cause an exacerbation of the symptoms of the disorder. This possibility highlights the importance of the questions asked by this study.

We examined the impact of a biological explanation of generalized anxiety disorder on prognostic pessimism and attributions of personal responsibility among persons with and without symptoms of the disorder. The study involved systematically manipulating whether participants received a biological explanation of the disorder. The explanation was written in such a way as to facilitate the clear conclusion that the disorder had a biological cause. To our knowledge, this is the first study that has examined the consequences of experimentally varying the presence of a biological explanation of a specific mental disorder among individuals who report symptoms of the disorder. In light of existing research ( 8 , 9 ), we predicted that the biological explanation would decrease attributions of personal responsibility but increase prognostic pessimism.

Participants

Data were collected in January and February of 2012. Adults in the United States were recruited online through Amazon.com’s Mechanical Turk service (mTurk), which allows individuals to sign up for short tasks in exchange for small monetary payments ( 25 – 27 ). [Information about the use of mTurk for recruitment is available online as a data supplement to this article.]

All procedures were approved by the Institutional Review Board at Yale University and were administered online by using Qualtrics.com software. After providing informed consent, participants completed the Generalized Anxiety Disorder Questionnaire for DSM-IV (GADQ-IV), a reliable and validated measure of the diagnostic criteria for generalized anxiety disorder ( 28 ). During data analysis, we used the dichotomous diagnostic approach for scoring the GADQ-IV ( 29 ) and then grouped participants according to whether their GADQ-IV responses suggested the presence of generalized anxiety disorder. Participants were not told about this classification.

Participants were randomly assigned to either the control (N=175) or the biological (N=176) condition. All participants first read a paragraph about the symptoms of generalized anxiety disorder, which was taken from the National Institute of Mental Health’s online publication titled Anxiety Disorders ( 30 ). Those in the biological condition then read an empirically based biological explanation of generalized anxiety disorder. [Both descriptions are available in the online data supplement to this article.]

No information beyond the symptom description was presented to those in the control condition, in order to isolate the effects of adding a biological explanation. We chose not to include an alternative etiological explanation for the control condition because the main goal of the study was to examine potential effects of the current ascendancy of biological explanations of psychopathology. Thus we sought to compare attitudes among individuals whose causal understanding of generalized anxiety disorder was not manipulated with those of individuals who received information about the biology of the disorder. This comparison mirrored how people’s reactions to a disorder might change after assimilating new information about biological factors into their preexisting conceptualizations of the condition—an occurrence that is likely to become ever more frequent. Because nonbiological explanations of psychopathology do not appear to have enjoyed a rise in popularity similar to that of biological explanations, this study did not examine their effects.

After reading the text corresponding to their assigned condition, participants were asked to imagine a typical person with generalized anxiety disorder and answer questions about that person. Even participants whose GADQ-IV responses suggested the possible presence of generalized anxiety disorder were asked to rate a typical person with generalized anxiety disorder rather than themselves. We chose this approach because, for ethical reasons, we could not manipulate beliefs about the causes of participants’ own symptoms. Therefore, because the biological explanation applied to generalized anxiety disorder generally, it was more appropriate to measure their beliefs about a typical person with the disorder.

Dependent measures were presented in two counterbalanced blocks. Within each block, the order of questions was randomized. As participants made their responses, the information about generalized anxiety disorder that they had read earlier was displayed at the bottom of the screen for use as a reference.

One block concerned the prognosis of a typical person with generalized anxiety disorder. One item, “To what extent do you believe these symptoms are treatable?” was rated on a scale from 1, very treatable, to 7, very untreatable. The other two items assessed participants’ expectations regarding the duration of the person’s symptoms: “How long do you think this person would continue to experience these symptoms?” and “How long do you think it would take for these symptoms to go away completely?” Both items were rated on an 8-point scale, with 1 indicating less than a week; 2, one to two weeks; 3, two to four weeks; 4, one to six months; 5, six months to one year; 6, more than one year but not indefinitely; 7, more than five years but not indefinitely; and 8, indefinitely.

The other block measured the extent to which participants considered a typical person with generalized anxiety disorder to be personally responsible for his or her symptoms. The two items were “To what extent do you believe this person is personally responsible for having these symptoms?” and “If this person tried really hard, to what extent do you believe this person would get better?” Both items were rated on a scale from 1, not at all, to 7, completely.

Finally, participants provided basic demographic information and were fully debriefed that anxiety likely results from a combination of genetic, biochemical, environmental, and psychological factors. They also received resources for finding help for psychological difficulties.

The sample consisted of 351 adults (N=181 males; 52%) living in the United States and ranging in age from 18 to 73 years (mean±SD=31.3±10.9). [More information about the demographic characteristics of the participants is available in the online data supplement .] Ninety-three participants (26%) met the GADQ-IV diagnostic cutoff for generalized anxiety disorder (N=47, control condition; N=46, biological condition). Although this rate was considerably higher than the disorder’s estimated prevalence ( 1 ), it is consistent with other research that has found that rates of symptoms of anxiety disorder among mTurk users greatly exceed prevalence rates for the general population ( 31 ). Of the 258 participants who did not meet the diagnostic cutoff, exactly 50% (N=129) were assigned to each condition.

Among all participants, responses to the two items gauging personal responsibility were significantly correlated (r=.44, p<.001), so they were averaged to compute a responsibility score for each participant. The scoring range was the same as for the individual items, so that higher scores indicated stronger endorsement of the notion that a person with generalized anxiety disorder is responsible for his or her own symptoms. In addition, responses on the two items measuring expectations of symptom duration were significantly correlated (Spearman’s ρ=.76, p<.001), so they were averaged to compute duration scores. The scoring range was the same as for the individual items, so that higher scores indicated longer expected duration of symptoms—an indicator of more prognostic pessimism—for a typical person with generalized anxiety disorder. The correlation between duration scores and treatability ratings, while significant, was small (ρ=.13, p=.02), so treatability ratings were analyzed separately.

We then conducted 2×2 (biological versus control condition × met or did not meet the GADQ-IV diagnostic cutoff) analyses of variance (ANOVAs) using responsibility scores and treatability ratings as the dependent variables. Because of the ordinal nature of our duration variable, we analyzed it separately using independent-samples Mann-Whitney U tests.

Participants who met the GADQ-IV diagnostic cutoff had significantly lower mean±SE responsibility scores than participants who did not meet the cutoff (2.81±1.15 versus 3.40±1.30; F=15.07, df=1 and 347, p<.001). There was no significant difference between these two groups for treatability ratings. Participants who met the GADQ-IV diagnostic cutoff also had significantly higher duration scores (mean±SE=6.73±1.47, median=7) than those who did not (mean±SE=6.03±1.73, median=6) (p=.001).

Our hypotheses pertained principally to the effects of our experimental manipulations. Indeed, a comparison of duration scores indicated that participants in the biological condition expected symptoms of generalized anxiety disorder (mean=6.44±1.63, median=7) to last longer than did those in the control condition (mean=6.00±1.71, median=6) (p=.01). In addition, comparison of responsibility scores indicated that participants in the biological condition attributed less personal responsibility for symptoms of generalized anxiety disorder than did those in the control condition (3.09±1.24 versus 3.39±1.31; F=5.12, df=1 and 347, p=.02).

The ANOVAs revealed no significant condition × diagnostic cutoff interactions, indicating that the effect of our experimental manipulation on responsibility and treatability ratings was the same regardless of whether participants met the GADQ-IV diagnostic cutoff. Nonetheless, we specifically examined the effects of our manipulations among people who met criteria for generalized anxiety disorder, given the potential clinical implications of these results. This approach also allowed us to examine the effects of our experimental manipulation on duration scores of the subset of the sample who met the cutoff. Indeed, an independent-samples Mann-Whitney U test of this subset revealed that those in the biological condition had significantly higher duration scores (mean±SE=7.10±1.20, median=7.75) than those in the control condition (mean±SE=6.36±1.61, median=6.5) (p=.02) ( Figure 1 ). Notably, half of participants in the biological condition who met the GADQ-IV cutoff had the maximum duration score.

a Duration scores indicate expected symptom duration. Possible scores range from 1 to 8, with higher scores indicating expectations of longer duration. Error bars represent plus or minus 1 standard error.

In addition, an independent-samples t test comparing mean responsibility scores among participants who met the cutoff found that those in the biological condition had significantly lower scores than those in the control condition, indicating that they attributed marginally less individual responsibility to a typical person with generalized anxiety disorder (2.60±1.09 versus 3.02±1.19, t=1.79, df=91, p=.08 ( Figure 2 ).

a Responsibility scores indicate the extent to which a person with generalized anxiety disorder is considered personally responsible for his or her symptoms. Possible scores range from 1, not at all, to 7, completely. Error bars represent plus or minus 1 standard error.

To our knowledge, this study is the first to compare the effects of experimental manipulation of exposure to biological explanations of a mental disorder among people with and without symptoms of the disorder. As predicted, we found that among both people with and people without symptoms of generalized anxiety disorder, the biological explanation decreased ascriptions of personal responsibility and blame but increased prognostic pessimism.

These findings suggest that caution is warranted in disseminating biological explanations of generalized anxiety disorder, for example, in public health campaigns or in the clinical delivery of psychoeducation. An increase in biological conceptualizations of anxiety could encourage the belief that conditions like generalized anxiety disorder are relatively immutable. Among people with generalized anxiety disorder—who already have a tendency toward worrying and anticipating adversity—this belief could have negative implications for their chances of recovery ( 17 , 18 ).

Even our finding that biological explanations decreased ascriptions of personal responsibility for generalized anxiety disorder could be seen as a double-edged sword, reducing blame but also suggesting that persons with anxiety disorders lack control over their psyches. Indeed, one of the items assessing responsibility asked about the extent to which a typical person with generalized anxiety disorder could overcome the disorder “if this person tried really hard.” If biological explanations create or exacerbate the perception that effort to overcome one’s anxiety is likely to be futile, this could potentially decrease motivation to engage with treatment (an effortful process), which could in turn have negative clinical consequences ( 20 ).

Treatability was the only dependent variable for which we did not find a significant effect for the biological explanation. One explanation may be that biological explanations of psychopathology tend to increase the perception that medication is effective but tend to decrease the perception that psychotherapy is effective ( 32 ). If our biological explanation of generalized anxiety disorder made some potential treatments seem more efficacious while making others seem less so, these effects could have canceled each other out, leading to an overall null effect. The small correlation between treatability ratings and duration scores, and the fact that our experimental manipulation significantly affected the latter but not the former, could be explained by differences in the wording of the questions. Perhaps the participants’ duration scores reflected their expectations regarding the prognosis of generalized anxiety disorder in the absence of any treatment, given that the items assessing expectations of duration did not mention treatment. Treatability ratings, on the other hand, may pertain more to participants’ beliefs about whether treatment, once employed, would be likely to be effective.

One limitation of this study was that all participants, including those whose GADQ-IV responses indicated the potential presence of generalized anxiety disorder, were asked to answer items related to the dependent measures while imagining a typical person with generalized anxiety disorder, so we cannot conclude definitively that the biological explanation influenced any participants’ beliefs about their own symptoms of anxiety. Nonetheless, the biological explanation affected their general perceptions of the disorder, which would likely influence how they would react if given a diagnosis of generalized anxiety disorder and biological explanations for it. In addition, all participants read the information about generalized anxiety disorder and answered questions about it immediately after completing the GADQ-IV, so they were likely to still have had their own anxiety in mind while completing the items pertaining to the dependent measures.

In this study, we compared attitudes toward generalized anxiety disorder among participants who received a biological explanation of the disorder versus those who received only a description of the disorder’s symptoms. We used this contrast to isolate the impact of learning new biological information. Nonetheless, our data can be used to draw conclusions only about the effects of the biological explanation compared with no causal explanation. It is conceivable that other causal accounts that place the symptoms of psychopathology outside the control of affected individuals could have effects similar to those of a biological explanation. However, this would likely depend greatly on which nonbiological causal factors were being considered, given that they might vary significantly in the extent to which they are perceived to be under individual control. The comparison used in this study avoided any potential confounding effects that could result from the idiosyncrasies of choosing a particular causal explanation as an alternative to the biological one. However, future research could specifically examine the extent to which biological explanations have unique consequences.

These findings highlight the potential negative consequences of biological explanations of mental disorders on prognostic expectations, both among members of the general public and individuals with symptoms of the disorder. An important direction for future research will be to explore ways of presenting biological explanations of mental disorders without yielding prognostic pessimism. Recent trends ( 6 ) suggest that public endorsement of biological explanations of psychopathology is likely to continue to increase. However, contemporary research has shown that the influence of biology on mental health is anything but deterministic ( 33 – 35 ). Recent evidence has suggested that some of the negative effects of biological explanations of psychopathology can be eliminated by pairing such explanations with information about how mental disorders can be successfully treated ( 36 ). Perhaps helping the public to understand the malleable nature of biology can help to break the psychological link between biological explanations and prognostic pessimism ( 22 ). If so, current trends toward neural and genetic conceptions of psychopathology need not lead to detrimental beliefs among people with and without mental problems.

Acknowledgments and disclosures

This study was supported by grant R01 MH57737 from the National Institute of Mental Health.

The authors report no competing interests.

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COGNITIVE THEORY AND MODELS OF ANXIETY: AN INTRODUCTION

COGNITIVE THEORY OF ANXIETY DISORDERS In anxiety disorder the disturbance in information processing which underlies anxiety vulnerability and anxiety maintenance can be viewed as a preoccupation with or ‘fixation’ on the concept of danger, and an associated underestimation of personal ability to cope (Beck, Emery & Greenberg, 1985). The theme of danger in anxiety is evident in the content of anxious schemas (i.e. assumptions and beliefs) and the content of negative automatic thoughts. The predominance of danger-related thoughts in the stream of consciousness of anxiety patients (e.g. Beck, Laude & Bohnert, 1974a; Hibbert, 1984; Rachman, Lopatka & Levitt, 1988), contrasts with the themes of loss and self-devaluation in depressive negative automatic thoughts (e.g. Beck, Rush, Shaw & Emery, 1979; Beck, 1987), and is the basis of the content-specificity hypothesis in which anxiety and depression are distinguishable in terms of thought content. The overestimation of danger and underestimation of ability to cope with situations in anxiety disorder reflects the activation of underlying danger schemas: ‘The locus of the disorder in the anxiety states is not in the affective system but in the hypervalent cognitive schemas relevant to danger that are continually presenting a view of reality as dangerous and the self as vulnerable’ (Beck, 1985, p. 192). Once danger appraisals are activated a number of vicious circles maintain anxiety. Particular anxiety symptoms may themselves pose a threat. For example, they may impair performance or be interpreted as a sign of serious physical or mental disorder. These effects increase the subjective sense of vulnerability, and as appraisals of danger increase so do primal anxiety responses which in turn contribute to unfavourable responses and appraisals, and so on. Dysfunctional schemas The term schema refers to a cognitive structure. However, in the schema theory of emotional disorder it is the content of these structures which is given most consideration. Two types of informational content or knowledge at the schema level are considered in Beck’s theory: beliefs and assumptions . Beliefs are ‘core’ constructs that are unconditional in nature (e.g. ‘I’m a failure; I’m worthless; I’m vulnerable; I’m inferior’), and are taken as truths about the self and the world. Assumptions are conditional and may be thought of as instrumental, insomuch as they represent contingencies between events and self-appraisals (e.g. ‘if I show signs of anxiety then people will think I’m inferior; having bad thoughts means I am a bad person; unexplained physical symptoms are usually a sign of serious illness; if I can’t control anxiety I am a complete failure’). Beliefs are typically expressed as unconditional self-relevant statements (e.g. ‘I am a failure’), whereas assumptions are expressed as ‘if-then’ propositions (e.g. if I show signs of anxiety then everyone will reject me’). The maladaptive schemas that characterise emotional disorder are hypothesised as more rigid, inflexible and concrete than schemas of normal individuals (Beck, 1967). The content of a schema is purported to be specific to a disorder. Therefore, anxiety schemas contain assumptions and beliefs about danger to one’s personal domain (Beck et al., 1985) and of one’s reduced ability to cope. Specific models of disorders such as panic (Clark, 1986), Social phobia (Clark & Wells, 1995), and Generalised Anxiety Disorder (Wells, 1995), identify more specific themes in appraisal and schemas associated with problem maintenance. In generalised anxiety, for example, a disorder characterised by chronic worry, beliefs about general inability to cope, and positive and negative beliefs about worrying itself, have been implicated (Wells, 1995). In panic disorder, in which patients show a tendency to misinterpret bodily sensations in a catastrophic way, appraisals and assumptions concerning the dangerous nature of anxiety symptoms and other bodily events predominate (Clark, 1986). In the specific phobias individuals associate a situation or object with danger and hold assumptions concerning the negative events that could occur when exposed to the phobic stimulus (Beck et al., 1985). Although dysfunctional assumptions and beliefs may form as a result of early experience this is not always the case. In panic disorder, for example, dysfunctional assumptions may not pre-date the first panic attack, but may develop as a consequence of how the attack was dealt with (Clark, personal communication). If, for example, the individual is led to believe that panic attacks can lead to negative events such as fainting, or the person is presented with ambiguous information concerning his or her state of health, dysfunctional assumptions are likely to be established. In generalised anxiety, patients seem to hold positive and negative beliefs about worrying (Wells, 1995). Positive beliefs in some cases are derived from early experience, and negative beliefs about worrying only develop after an extended time period, perhaps when attempts to control worry seem impaired. In social phobia, some patients may function well most of their lives but develop specific negative assumptions about the social self only after they fail to meet up to personal rules for social self-regulation (Clark & Wells, 1995; Wells & Clark, 1997). In other cases negative beliefs about the social self may be longstanding and are associated with shyness and timidity since childhood. Assumptions or ‘rules’ in anxiety influence the conclusions individuals draw from situations and also the manner in which they behave. For example, a socially anxious patient with the assumption ‘Showing anxiety will lead people not to take me seriously’ may reach the conclusion ‘I had better say as little as possible in order to conceal my anxiety’; this may lead to the self-instruction ‘Don’t say a lot; try and look relaxed’. In this scenario the linkages between assumptions, situational appraisals and behavioural imperatives are observable. As discussed later in this chapter, behavioural responses emerging from dysfunctional appraisals and assumptions are often involved in the maintenance of belief in danger appraisals, assumptions, and beliefs (Salkovskis, 1991; Wells et al., 1995b). Negative automatic thoughts, worries and obsessions The content of cognition in emotional disorders has been given various labels, such as automatic thoughts (Beck, 1967), self-statements (Meichenbaum, 1977), and worry (Borkovec, Robinson, Pruzinsky & De Pree, 1983a). In Beck’s schema theory of anxiety, negative automatic thoughts represent the surface cognitive features of schema activation. Negative automatic thoughts (NATs) are appraisals or interpretations of events, and can be tied to particular behavioural and affective responses. A strong cognitive position would argue that negative automatic thoughts cause anxiety, however, in schema theory they are considered to reflect cognitive mechanisms that modulate and maintain anxiety. The description of negative automatic thoughts provided by Beck and colleagues (e.g. Beck et al., 1985) suggests that they are rapid negative thoughts that can occur outside of the focus of immediate awareness although they are amenable to consciousness. They occur in verbal or imaginal form, and are believable at the time of occurrence. Distinctions can be made between different types of thought in anxiety disorders. More specifically, negative automatic thoughts can be distinguished from worry, and obsessions. Wells (1994a) suggests that it may be useful to distinguish between all these varieties of thought. For example, negative automatic thoughts can be distinguished from worry, and both worry and negative automatic thoughts can be distinguished from obsessions (Wells, 1994a; Wells & Morrison, 1994) . Worry is described by Borkovec and colleagues (Borkovec et al., 1983) as a chain of negatively affect laden thoughts aimed at problem solving. Borkovec et al. (1983a) contend that worry is predominantly a verbally based thought process; however, negative automatic thoughts can occur in a verbal and an imaginal form. Obsessions tend to be of shorter duration than worries, but most relevant of all they are ego-dystonic whereas worries and NATs are not—that is, they are experienced as senseless and alien to the self-concept. For example, a mother may have thoughts of harming her newborn baby although she has no desire to do so. In general, NATs and worries represent appraisals of events in cognitive models of anxiety, while obsessions are intrusive mental experiences that are the focus of appraisals. Obsessions occur as urges or impulses as well as thoughts (e.g. Parkinson & Rachman, 1981). Worries are normal phenomena (Wells & Morrison, 1994), as are obsessions (Rachman & de Silva, 1978; Salkovskis & Harrison, 1984), and automatic thoughts are also likely to be a normally occurring type of cognition. Wells and Morrison (1994) compared the attributes of normally occurring worries and obsessions over a two-week period in non-patient subjects. Their data showed significant self-rated differences between these two types of thought. Worries were rated as significantly more verbal and obsessions as more imaginal; worries were also of longer duration (overall mean = 9 minutes for worries and 2 minutes for obsessions), worries were less involuntary, and more realistic than obsessions. These data suggest that distinctions between different types of thought are possible. In Chapters 8 and 10 the theoretical and practical relevance of potential distinctions is considered in detail. The role of behaviour When a danger appraisal is made the cognitive system facilitates caution by eliciting a series of self-doubts, negative evaluations, and negative predictions. The somatic manifestation of this consists of a range of feelings such as unsteadiness, faintness, and weakness. Beck et al. (1985) assume that this is part of a primal survival mechanism that exists to terminate risk-taking behaviour and orient behaviour towards self-protection. In some circumstances such as social performance situations these responses can increase the danger they are designed to avert (i.e. they interfere with social performance). Apart from automatic and reflexive anxiety responses highlighted in the schema model, behavioural reactions that are more volitional in nature are an important influence in the maintenance of dysfunction. Wells and Matthews (1994) suggest that many of the cognitive and behavioural responses to threat reflect strategies or plans of action that are actively (at least initially) executed and modified by the individual to protect against danger. Unfortunately some of these responses are counterproductive because they maintain preoccupation with threat and prevent unambiguous disconfirmation of dysfunctional thoughts and assumptions (Salkovskis, 1991; Wells et al., 1995b). For example, a social phobic fearful of babbling and talking incoherently in a social situation may focus more attention on the self and monitor his/her spoken words closely. In addition to this cognitive selfmonitoring strategy there may be attempts to pronounce words in a clear and controlled way, and rehearse mentally the material to be spoken before speaking in order to check that it sounds acceptable. These subtle and covert responses constitute ‘safety behaviours’ (Salkovskis, 1991) that are intended to avert feared events. Safety behaviours play a significant role in the maintenance of anxiety. For example, a person having a panic attack who believes that a catastrophe such as fainting is imminent is likely to engage in behaviour designed to prevent the catastrophe, such as sitting down or trying to relax. Whilst the behaviour may relieve anxiety it unintentionally preserves the belief in the catastrophe. Under these conditions each panic becomes an example of a ‘near-miss’ rather than a disconfirmation of belief, and danger may seem subsequently more evident. In some instances safety behaviours not only prevent exposure to disconfirmatory experiences, but exacerbate symptoms in a way that enhances belief in danger appraisals. In social phobia, attempts to monitor one’s own speech and mentally censor sentences before saying them interferes with processing important aspects of the situation and interferes with subjective verbal fluency, thereby contributing to appraisals of poor performance (e.g. Wells et al., 1995b). Similarly, attempts to suppress certain types of thought, have been shown to increase the frequency of the unintended thought (Wegner, Schneider, Carter & White, 1987). This effect has implications for disorders characterised by unwanted intrusive thoughts, in particular obsessional problems and generalised anxiety disorder. In these cases individual attempts to control or suppress obsessions or worries may exacerbate these thoughts. In summary, it is likely that safety behaviours maintain anxiety via a number of pathways: 1. Safety behaviours exacerbate bodily symptoms — an effect that may be interpreted as evidence for feared catastrophes. For example, controlling one’s breathing may lead to hyperventilation and the symptoms associated with respiratory alkalosis. Controlling certain thoughts may contribute to paradoxical effects of increased preoccupation with thoughts and concomitant diminished appraisals of control. 2. The non-occurrence of feared outcomes can be attributed to the use of the safety behaviour rather than correctly attributed to the fact that catastrophe will not occur. 3. Particular safety behaviours, such as increased vigilance for threat, reassurance seeking, etc., enhance exposure to danger-related information that strengthens negative beliefs. For example, the health-anxious patient may seek reassurance from numerous medical consultations, increasing the likelihood of exposure to contradictory and ambiguous information. This information may then be interpreted as evidence that ‘doctors tend to miss serious illness’ which strengthens danger appraisals and disease conviction. 4. Safety behaviours may contaminate social situations and affect interactions in a manner consistent with negative appraisals. The social phobic who elects to say little about the self and avoid eye contact in order to reduce a risk of appearing ‘foolish’ is difficult to make conversation with. This may lead people to interact less with the social phobic and exclude them from conversation. This effect could then be interpreted by the social phobic as evidence that people really think he or she is foolish. Wells et al. (1995b) document a range of safety behaviours tied to specific fears of social phobics (see Chapter 7 and the rating scales in the Appendix for examples). Cognitive biases Once activated, danger schemata introduce biases in the processing of information. These biases are often distortions that affect interpretations of events in a way that is consistent with the content of dysfunctional schemas. As a result, negative beliefs and appraisals are maintained. Biases in processing include attentional phenomena such as selective attention for threat-related material, and biases in the interpretation of events. Beck and associates, and Burns (1989) have labelled a range of interpretive biases as ‘thinking errors’ or ‘cognitive distortions’ (Beck et al., 1979, 1985; Beck, 1967; Burns, 1989). Common errors or distortions include the following: Arbitrary inference: Drawing a conclusion in the absence of sufficient evidence. Selective abstraction: Focusing on one aspect of a situation while ignoring more important (and more relevant) features. Overgeneralisation: Applying a conclusion to a wide range of events or situations when it is based on isolated incidents. Magnification/minimisation: Enlarging or reducing the importance of events. Minimisation is similar to discounting the positives—insisting that positive experiences don’t count. Personalising: Relating external events to the self when there is no obvious basis to do so. Catastrophising: Dwelling on the worst possible outcome of a situation and overestimating the probability that it will occur. Mind reading: Assuming people are reacting negatively to you when there is no definite evidence for this. To illustrate how cognitive biases can maintain belief in negative interpretations, consider the example of a socially phobic person involved in a conversation with a work colleague. The colleague suddenly cuts short the conversation and leaves the situation. The social phobic may interpret this as: ‘I must be so boring’ or ‘he thinks I’m an idiot, he doesn’t like me’. These appraisals are examples of ‘ arbitrary inference ’ and ‘ mind reading ’. In the next encounter with the colleague the social phobic is pre-occupied with negative thoughts about ‘appearing boring and idiotic’, he/she selectively attends to his/her own anxious performance, and fails to notice positive signals from the work colleague, or discounts these as evidence that he is ‘just trying to be nice’. In this example biases of attention and inference serve to maintain belief in negative appraisals, as negative information is abstracted, and positive information is not processed, or is discounted. SUMMARY OF THE GENERAL SCHEMA THEORY The central principles of schema theory of anxiety were outlined in the previous sections. In summary, anxiety is associated with appraisals of danger. Some individuals are more susceptible to appraising situations as dangerous because they possess schemas containing information about the dangerous meaning of situations and about their diminished ability to deal effectively with threat. Once ‘danger schemas’ are activated, appraisals are characterised by negative automatic thoughts about danger. These thoughts reflect themes of physical, social or psychological catastrophes directly or indirectly involving the self. Biases in processing associated with schema activation maintain belief in negative automatic thoughts, assumptions and beliefs by distorting interpretations in a manner that is consistent with dysfunctional beliefs and appraisals. Individuals typically try to reduce danger through their behavioural responses of avoidance or safety-behaviours. These behaviours cause their own problems in anxiety disorders by intensifying anxiety symptoms, and preventing disconfirmation of belief in danger cognitions. The basic features of this generic cognitive theory are depicted diagrammatically in Figure 1.0 . Figure 1.0 Generic cognitive theory of anxiety disorder

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