A history of anxiety: from Hippocrates to DSM

This article describes the history of the nosology of anxiety disorders. Greek and Latin physicians and philosophers distinguished anxiety from other types of negative affect, and identified it as a medical disorder. Ancient Epicurean and Stoic philosophers suggested techniques to reach an anxiety-free state of mind that are reminiscent of modern cognitive psychology. Between classical antiquity and the late 19^th century there was a long interval during which anxiety was not classified as a separate illness. However, typical cases of anxiety disorders kept being reported, even if under different names. In the 17^th century, Robert Burton described anxiety in The Anatomy of Melancholy. Panic attacks and generalized anxiety disorder may be recognized in the “panophobias” in the nosology published by Boissier de Sauvages in the 18^th century. Also, anxiety symptoms were an important component of new disease constructs, culminating in neurasthenia in the 19^th century. Emil Kraepelin devoted much attention to the possible presence of severe anxiety in manic-depressive illness, thereby anticipating the “anxious distress” specifier of bipolar disorders in DSM-5. A pitfall to consider is that the meaning of common medical terms, such as melancholia, evolves according to places and epochs.     

A perspective on the current issues in the DSM-5 classification of personality disorders

David Kupfer chaired the DSM-5 Task Force, and Andrew Skodol the working group, on personality disorders. Various initial propositions were posted on the Internet in 2010 for comment and discussion: new general definition, new criteria, new diagnostic procedures, reduction in the number of categories, and dimensional representation. Following numerous criticisms, the Task Force''s final decisions were made public on December 1, 2012. Personality disorders now figure alongside other mental disorders, because of the deletion of Axis II. The methodology concerning personality traits is in a third section to promote new studies. The new proposed hybrid system has not, to date, proven better than the categories of the DSM-IV. These various decisions are commented upon.     

The rise of moral emotions in neuropsychiatry

Clinical psychopathology has largely ignored the developments in the field of social neuroscience. The so-called moral emotions are a group of affective experiences thought to promote cooperation, group cohesion, and reorganization. In this review, we: (i) briefly describe a provisional taxonomy of a limited set of moral emotions and their neural underpinnings; and (ii) discuss how disgust, guilt, anger/indignation, and shame/embarrassment can be conceptualized as key affective experiences in different neuropsychiatric disorders. Based on a concise review of the literature linking moral emotions, psychopathology, and neuropsychiatry, we have devised a simple and preliminary scheme where we conjecture how specific moral emotions can be implicated in some categories of DSM-5 diagnoses, potentially helping to bridge psychopathology and neurobiologically plausible variables, in line with the Research Domain Criteria initiative. We hope this stimulates new empirical work exploring how moral emotional changes and their underlying neurobiology can help elucidating the neural underpinnings of mental disorders.     

Cognitive-behavioral therapy for anxiety disorders: an update on the empirical evidence

A large amount of research has accumulated on the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for anxiety disorders including posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, social anxiety disorder, and specific phobia. The purpose of the current article is to provide an overview of two of the most commonly used CBT methods used to treat anxiety disorders (exposure and cognitive therapy) and to summarize and discuss the current empirical research regarding the usefulness of these techniques for each anxiety disorder. Additionally, we discuss the difficulties that arise when comparing active CBT treatments, and we suggest directions for future research. Overall, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but dismantling studies are needed to determine which specific treatment components lead to beneficial outcomes and which patients are most likely to benefit from these treatment components.     

A lifespan view of anxiety disorders

Neurodevelopmental changes over the lifespan, from childhood through adulthood into old age, have important implications for the onset, presentation, course, and treatment of anxiety disorders. This article presents data on anxiety disorders as they appear in older adults, as compared with earlier in life. In this article, we focus on aging-related changes in the epidemiology, presentation, and treatment of anxiety disorders. Also, this article describes some of the gaps and limitations in our understanding and suggests research directions that may elucidate the mechanisms of anxiety disorder development later in life. Finally we describe optimal management of anxiety disorders across the lifespan, in "eight simple steps" for practitioners.     

Sleep and anxiety disorders

Sleep disturbances-particularly insomnia - are highly prevalent in anxiety disorders and complaints such as insomnia or nightmares have even been incorporated in some anxiety disorder definitions, such as generalized anxiety disorder and posttraumatic stress disorder. In the first part of this review, the relationship between sleep and anxiety is discussed in terms of adaptive response to stress. Recent studies suggested that the corticotropin-releasing hormone system and the locus ceruleus-autonomic nervous system may play major roles in the arousal response to stress. It has been suggested that these systems may be particularly vulnerable to prolonged or repeated stress, further leading to a dysfunctional arousal state and pathological anxiety states, Polysomnographic studies documented limited alteration of sleep in anxiety disorders. There is some indication for alteration in sleep maintenance in generalized anxiety disorder and for both sleep initiation and maintenance in panic disorder; no clear picture emerges for obsessive-compulsive disorder or posttraumatic stress disorder. Finally, an unequivocal sleep architecture profile that could specifically relate to a particular anxiety disorder could not be evidenced; in contrast, conflicting results are often found for the same disorder. Discrepancies between studies could have been related to illness severity, diagnostic comorbidity, and duration of illness. A brief treatment approach for each anxiety disorder is also suggested with a special focus on sleep.     

Cognitive behavioral therapy in anxiety disorders: current state of the evidence

A plethora of studies have examined the efficacy and effectiveness of cognitive-behavioral therapy (CBT) for adult anxiety disorders. In recent years, several meta-analyses have been conducted to quantitatively review the evidence of CBT for anxiety disorders, each using different inclusion criteria for studies, such as use of control conditions or type of study environment. This review aims to summarize and to discuss the current state of the evidence regarding CBT treatment for panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Overall, CBT demonstrates both efficacy in randomized controlled trials and effectiveness in naturalistic settings in the treatment of adult anxiety disorders. However, due to methodological issues, the magnitude of effect is currently difficult to estimate. In conclusion, CBT appears to be both efficacious and effective in the treatment of anxiety disorders, but more high-quality studies are needed to better estimate the magnitude of the effect.     

Epidemiology of anxiety disorders in the 21st century

Anxiety disorders, including panic disorder with or without agoraphobia, generalized anxiety disorder, social anxiety disorder, specific phobias, and separation anxiety disorder, are the most prevalent mental disorders and are associated with immense health care costs and a high burden of disease. According to large population-based surveys, up to 33.7% of the population are affected by an anxiety disorder during their lifetime. Substantial underrecognition and undertreatment of these disorders have been demonstrated. There is no evidence that the prevalence rates of anxiety disorders have changed in the past years. In cross-cultural comparisons, prevalence rates are highly variable. It is more likely that this heterogeneity is due to differences in methodology than to cultural influences. Anxiety disorders follow a chronic course; however, there is a natural decrease in prevalence rates with older age. Anxiety disorders are highly comorbid with other anxiety disorders and other mental disorders.     

The history of nosology and the rise of the Diagnostic and Statistical Manual of Mental Disorders

The current Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 arose from a tradition filled with haphazard science and politically driven choices. The nosology of modern psychiatry began with the German classifiers of the late 19th century, especially Emil Kraepelin. Psychoanalysis then blotted out the classificatory vision for the next half-century, and most of this European psychopathological science failed to cross the Atlantic. The DSM series was a homegrown American product, beginning with Medical 203 in 1945, then guided by psychoanalytic insights through DSM-I in 1952 and DSM-II in 1968. In 1980, DSM-III represented a massive “turning of the page” in nosology, and it had the effect of steering psychoanalysis toward the exit in psychiatry and the beginning of a reconciliation of psychiatry with the rest of medicine. With the advent of DSM-5, however, questions are starting to be asked about whether this massive venture is on the right track.     

A systematic review of the neural bases of psychotherapy for anxiety and related disorders

Brain imaging studies over two decades have delineated the neural circuitry of anxiety and related disorders, particularly regions involved in fear processing and in obsessive-compulsive symptoms. The neural circuitry of fear processing involves the amygdala, anterior cingulate, and insular cortex, while cortico-striatal-thalamic circuitry plays a key role in obsessive-compulsive disorder. More recently, neuroimaging studies have examined how psychotherapy for anxiety and related disorders impacts on these neural circuits. Here we conduct a systematic review of the findings of such work, which yielded 19 functional magnetic resonance imaging studies examining the neural bases of cognitive-behavioral therapy (CBT) in 509 patients with anxiety and related disorders. We conclude that, although each of these related disorders is mediated by somewhat different neural circuitry, CBT may act in a similar way to increase prefrontal control of subcortical structures. These findings are consistent with an emphasis in cognitive-affective neuroscience on the potential therapeutic value of enhancing emotional regulation in various psychiatric conditions.     

The epidemiology of anxiety disorders: a review

Epidemiological studies show that anxiety disorders are highly prevalent and an important cause of functional impairment; they constitute the most frequent menial disorders in the community. Phobias are the most common with the highest rates for simple phobia and agoraphobia. Panic disorder (PD) and obsessive-compulsive disorder (OCD) are less frequent (2% lifetime prevalence), and there are discordant results for social phobia (SP) (2%-16%) and generalized anxiety disorder (GAD) (3%-30%). These studies underline the importance of an accurate definition of disorders using unambiguous diagnostic and assessment criteria. The boundaries between anxiety disorders are often ill defined and cases may vary widely according to the definition applied. Simple phobia, agoraphobia, and GAD are more common in vmrnen, while there is no gender différence for SP, PD, and OCD, Anxiety disorders are more common in separated, divorced, and widowed subjects; their prevalence is highest in subjects aged 25 to 44 years and lowest in subjects aged >65 years. The age of onset of the different types of anxiety disorders varies widely: phobic disorders begin early in life, whereas PD occurs in young adulthood. Clinical - rather than epidemiological - studies have examined risk factors such as life events, childhood experiences, and familial factors. Anxiety disorders have a chronic and persistent course, and are frequently comorbid with other anxiety disorders, depressive disorders, and substance abuse. Anxiety disorders most frequently precede depressive disorders or substance abuse, Comorbid diagnoses may influence risk factors like functional impairment and quality of life. It remains unclear whether certain anxiety disorders (eg, PD) are risk factors for suicide. The comorbidity of anxiety disorders has important implications for assessment and treatment and the risk factors should be explored. The etiology, natural history, and outcome of these disorders need to be further addressed in epidemiological studies.     

Psychopharmacology of anxiety disorders

Exposure of the general population to a 1:4 lifetime risk of disabling anxiety has inspired generations of fundamental and clinical psychopharmacologists, from the era of the earliest benzodiazepines (BZ) to that of the selective serotonin reuptake inhibitors (SSRIs) and related compounds, eg, the serotonin and norepinephrine reuptake inhibitors (SNRIs). This comprehensive practical review summarizes current therapeutic research across the spectrum of individual disorders: generalized anxiety disorder (GAD), panic disorder (PD) and agoraphobia (social anxiety disorder), compulsive disorder (OCD), phobic disorder (including social phobia), and posttraumatic stress disorder (PTSD). Specific diagnosis is a precondition to successful therapy: despite substantial overlap, each disorder responds preferentially to specific pharmacotherapy. Comorbidity with depression is common; hence the success of the SSRIs, which were originally designed to treat depression. Assessment (multidomain measures versus individual end points) remains problematic, as-frequently-do efficacy and tolerability The ideal anxiolytic remains the Holy Grail of worldwide psychopharmacologic research.     

Dimensional anxiety scales for DSM-5: Sensitivity to clinical severity

PurposePsychometric properties and clinical sensitivity of brief self-rated dimensional scales to supplement categorical diagnoses of anxiety disorders in the DSM-5 were recently demonstrated in a German treatment seeking sample of adults. The present study aims to demonstrate sensitivity of these scales to clinical severity levels.MethodsThe dimensional scales were administered to 102 adults at a university outpatient clinic for psychotherapy. Diagnostic status was assessed using the Munich-Composite International Diagnostic Interview. To establish a wide range of clinical severity, we considered subthreshold (n = 83) and threshold anxiety disorders (n = 49, including Social Phobia, Specific Phobia, Agoraphobia, Panic Disorder, and Generalized Anxiety Disorder).ResultsIndividuals with either subthreshold or threshold anxiety disorder scored higher on all dimensional scales relative to individuals without anxiety. In addition, individuals with a threshold anxiety disorder scored higher on the dimensional scales than individuals with a subthreshold anxiety disorder (except for specific phobia). Disorder-related impairment ratings, global functioning assessments and number of panic attacks were associated with higher scores on dimensional scales. Findings were largely unaffected by the number of anxiety disorders and comorbid depressive disorders.ConclusionThe self-rated dimensional anxiety scales demonstrated sensitivity to clinical severity, and a cut-off based on additional assessment of impairment and distress may assist in the discrimination between subthreshold and threshold anxiety disorders. Findings suggest further research in various populations to test the utility of the scales for use in DSM-5.     

Cognitive behavioral group therapy for anxiety: recent developments

Anxiety disorders occur frequently, and can have a negative impact on the quality of people''s lives. They often begin at an early age and can have some serious consequences. This article is an overview of the recent studies concerning group cognitive-behavioral interventions for anxiety disorders. In the last few years, anxiety disorder prevention for children and adolescents has become an important focus of research work. Group prevention programs are based on standard cognitive behavioral therapy (CBT) strategies and are aimed at preventing anxiety disorders as early as possible. Numerous cognitive behavioral group therapies for children as well as adults have been well studied. There are many CBT protocols that have been developed for treating specific anxiety disorders. Now, specialized CBT programs are available for individuals who suffer from different anxiety disorders, enabling them to be treated together in groups.     

CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders

Background

Neurodevelopmental disorders are impairments of brain function that affect emotion, learning, and memory. Copy number variations of contactin genes (CNTNs), including CNTN3, CNTN4, CNTN5, and CNTN6, have been suggested to be associated with these disorders. However, phenotypes have been reported in only a handful of patients with copy number variations involving CNTNs.

Methods

From January 2009 to January 2013, 3724 patients ascertained through the University of Pittsburgh Medical Center were referred to our laboratory for clinical array comparative genomic hybridization testing. We screened this cohort of patients to identify individuals with the 3p26.3 copy number variations involving the CNTN6 gene, and then retrospectively reviewed the clinical information and family history of these patients to determine the association between the 3p26.3 copy number variations and neurodevelopmental disorders.

Results

Fourteen of the 3724 patients had 3p26.3 copy number variations involving the CNTN6 gene. Thirteen of the 14 patients with these CNTN6 copy number variations presented with various neurodevelopmental disorders including developmental delay, autistic spectrum disorders, seizures and attention deficit hyperactivity disorder. Family history was available for 13 of the 14 patients. Twelve of the thirteen families have multiple members with neurodevelopmental and neuropsychiatric disorders including attention deficit hyperactivity disorder, seizures, autism spectrum disorder, intellectual disability, schizophrenia, depression, anxiety, learning disability, and bipolar disorder.

Conclusions

Our findings suggest that deletion or duplication of the CNTN6 gene is associated with a wide spectrum of neurodevelopmental behavioral disorders.     

Psychophysiological assessment of stress reactivity and recovery in anxiety disorders

The present study aimed to examine changes in psychophysiological arousal from baseline to a stressor phase (reactivity) and from the stressor phase to a second resting phase (recovery) in patients with anxiety disorders. Fifty adult patients with DSM-5 anxiety disorders (panic disorder, generalized anxiety disorder, or social anxiety disorder) and 28 healthy control (HC) participants underwent psychophysiological monitoring including electrocardiogram, respiration rate, electrodermal activity, gastrocnemius electromyograph, and end-tidal CO₂ for a 3-min resting phase, a 6-min mild stressor phase, and a 3-min recovery phase. Anxious patients then went on to receive naturalistic cognitive-behavioral therapy (CBT) in a specialty outpatient clinic. Results for the reactivity phase indicated that compared to HCs, patients with social anxiety disorder exhibited heightened psychophysiological reactivity while patients with panic disorder and generalized anxiety disorder exhibited attenuated reactivity. Results for physiological recovery (return to baseline after the stressor was withdrawn) were mixed, but provided some support for slower autonomic recovery in patients with generalized anxiety disorder and panic disorder compared to HCs. Participants with all anxiety disorders exhibited diminished change in high frequency heart rate variability compared to HCs. Generally, psychophysiological reactivity and recovery were not associated with CBT outcome, though exploratory analyses indicated that greater respiration rate reactivity and stronger respiration rate recovery were associated with better CBT outcomes in patients with panic disorder.     

Neuroimaging in anxiety disorders

Over the last few years, neuroimaging techniques have contributed greatly to the identification of the structural and functional neuroanatomy of anxiety disorders. The amygdala seems to be a crucial structure for fear and anxiety, and has consistently been found to be activated in anxiety-provoking situations. Apart from the amygdala, the insula and anterior cinguiate cortex seem to be critical, and ail three have been referred to as the "fear network." In the present article, we review the main findings from three major lines of research. First, we examine human models of anxiety disorders, including fear conditioning studies and investigations of experimentally induced panic attacks. Then we turn to research in patients with anxiety disorders and take a dose look at post-traumatic stress disorder and obsessive-compulsive disorder. Finally, we review neuroimaging studies investigating neural correlates of successful treatment of anxiety, focusing on exposure-based therapy and several pharmacological treatment options, as well as combinations of both.