Biological predictors of pharmacological therapy in anxiety disorders

At least one third of patients with anxiety disorders do not adequately respond to available pharmacological treatment. The reason that some patients with anxiety disorders respond well, but others not, to the same classes of medication is not yet fully understood. It is suggested that several biological factors may influence treatment mechanisms in anxiety and therefore could be identified as possible biomarkers predicting treatment response. In this review, we look at current evidence exploring different types of treatment predictors, including neuroimaging, genetic factors, and blood-related measures, which could open up novel perspectives in clinical management of patients with anxiety disorders.     

Historical aspects of anxiety

"Anxiety" is a key term for behavioral, psychoanalytic, neuroendocrine, and psychopharmacological observations and theories. Commenting on its historical aspects is difficult, since history is properly a study of primary data. Unfortunately, much clinical anecdote does not correspond to factual records of a long time ago. Even reports of objective studies may suffer from allegiance effects. This essay therefore primarily reflects the personal impact of others' work against the background of my experiences, clinical and scientific. These lead me to question the assumption that "anxiety", as it exists in syndromal disturbances, is simply the quantitative extreme of the normal "anxiety" that occurs during the anticipation of danger. An alternative view that emphasizes dysfunctions of distinct evolved adaptive alarm systems is presented.     

Experimental animal models for the simulation of depression and anxiety

An impressive number of animal models to assess depression and anxiety are available today. However, the relationship between these models and the clinical syndromes of depression and anxiety is not always clear. Since human anxiety disorders represent a multifactorial phenomenon frequently comorbid with major depression and/or other psychiatric problems, the chance of creating animal models which consistently reflect the human situation is quite poor. When using experimental models to understand homologies between animal and human behavior, we have to consider the context in which an animal is investigated, and both the functional significance and relevance of the behavioral parameters that are quantified. Moreover, gender and interindividual and interspecies variabilities in behavioral responses to the test situation and in the sensitivity to pharmacological treatments are potential sources for confounding results. In the past, these aspects have been often neglected in preclinical approaches to behavioral pharmacology and psychopharmacology. A pragmatic approach of combined preclinical and clinical efforts is necessary to imitate one or more aspects relevant to pathological anxiety disorders and depression. The resulting models may identify central nervous processes regulating defined behavioral output, with the potential to develop more effective treatments.     

Medication dependence and anxiety

Anxiety disorders are common and costly psychiatric illnesses. Pharmacological treatment was enhanced with the introduction of benzodiazepines, which proved safer and more effective than older drugs. The risk of dependence, however, has made clinicians reluctant to use these medications. In fact, few patients appear to develop significant difficulties with these drugs, given how widely they are used. Careful planning for discontinuation of therapy is important. In addition, for some individuals, there appears to be a complex and as yet unelucidaied relationship between dependence on drugs or alcohol and anxiety. The newer antidepressants offer efficacy without abuse or dependence liability, but are expensive and have side effects that are intolerable for some patients. Pharmacological therapy for anxiety should be prescribed and managed so as to minimize any existing risk, while aiming to restore the patient to wellness in terms of symptoms and function.     

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.     

The overlap between anxiety,depression, and obsessive-compulsive disorder

The anxiety disorders include generalized anxiety disorder, specific phobia, social phobia, agoraphobia, and panic disorder. In addition to the specific symptoms of these disorders, there may be a common experience of anxiety and even dysphoria across the conditions, and of course recourse to the same drug or choice of drugs for treatment. This overlap probably occurs because of universal dimensions of distress or negative affectivity, a shared genetic predisposition, and a common neurobiology Evidence of shared genes is still based mainly on twin studies, but the shared neurobiology can be investigated directly by the investigation of emotional or cognitive bias either behaviorally or using functional brain imaging. This intermediate phenotype can then provide a substrate for understanding and developing medicines and psychological treatments.     

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.     

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.     

Neurobiologically informed treatment for adults with anorexia nervosa: a novel approach to a chronic disorder

Anorexia nervosa (AN) is a severe and debilitating disorder with significant medical and psychological sequelae. To date, there are no effective treatments for adults, resulting in high rates of chronicity, morbidity, and mortality. Recent advances in brain imaging research have led to an improved understanding of etiology and specific neurobiological mechanisms underlying symptoms. Despite this, there are no treatments focused on targeting symptoms using this empirically supported mechanistic understanding of the illness. Updated treatment approaches focused on targeting neurobiological mechanisms underlying core AN symptomatology are necessary to improve treatment out-comes for this population. Neurobiologically Enhanced With Family Eating Disorder Trait Response Treatment (NEW FED TR) is a neurobiologically informed treatment targeting key temperament constructs associated with the illness through the delivery of psychoeducation and skills training to patients and nominated carers.     

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.     

Animal models of anxiety disorders in rats and mice: some conceptual issues

Animal models can certainly be useful to find out more about the biological bases of anxiety disorders and develop new, more efficient pharmacological and/or behavioral treatments. However, many of the current "models of anxiety" in animals do not deal with pathology itself, but only with extreme forms of anxiety which are still in the normal, adaptive range. These models have certainly provided a lot of information on brain and behavioral mechanisms which could be involved in the etiology and physiopathology of anxiety disorders, but are usually not satisfactory when confronted directly with clinical syndromes. Further progress in this field will probably depend on the finding of endophenotypes which can be studied in both humans and animals with common methodological approaches. The emphasis should be on individual differences in vulnerability, which have to be included in animal models. Finally, progress will also depend on refining theoretical constructs from an interdisciplinary perspective, including psychiatry, psychology, behavioral sciences, genetics, and other neurosciences.     

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.     

Treatment-refractory anxiety; definition,risk factors,and treatment challenges

A sizable proportion of psychiatric patients will seek clinical evaluation and treatment for anxiety symptoms reportedly refractory to treatment. This apparent lack of response is either due to “pseudo-resistance” (a failure to have received and adhered to a recognized and effective treatment or treatments for their condition) or to true “treatment resistance.” Pseudo-resistance can be due to clinician errors in selecting and delivering an appropriate treatment effectively, or to patient nonadherence to a course of treatment. True treatment resistance can be due to unrecognized exogenous anxiogenic factors (eg, caffeine overuse, sleep deprivation, use of alcohol or marijuana) or an incorrect diagnosis (eg, atypical bipolar illness, occult substance abuse, attention deficit-hyperactivity disorder). Once the above factors are eliminated, treatment should focus on combining effective medications and cognitive behavioral therapy, combining several medications (augmentation), or employing novel medications or psychotherapies not typically indicated as first-line evidence-based anxiety treatments.     

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.     

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.     

On the role of corticotropin-releasing hormone receptors in anxiety and depression

On the basis of extensive basic and clinical studies, corticotropin-releasing hormone (CRH) and its related family members are considered to play a pivotal role in stress-related disorders, such as anxiety and depression. CRH is regarded as the principal mediator in the brain of the stress response, as it mediates neuroendocrine, autonomic, and behavioral responses to stressful challenges. Recently, this neuropeptide family has expanded due to the discovery of two new members, urocortin II (also termed stresscopin-related peptide) and urocortin III (also termed stresscopin), which are selective agonists for the CRH receptor type 2. They show a discrete neuroanatomical localization and are involved in stress-coping responses, such as anxiolysis. Here, on the basis of recent developments, we suggest that CRH, the urocortins, and their receptors form a complex system in the brain, which is recruited during both the acute and the recovery phases of the stress response.     

Separation anxiety: at the neurobiological crossroads of adaptation and illness

Physiological and adaptive separation anxiety (SA) is intimately connected with the evolutionary emergence of new brain structures specific of paleomammalians, the growth of neomammalian—and later hominid—brain and skull size, and the appearance of bipedalism. All these evolutionary milestones have contributed to expanding the behavioral repertoire and plasticity of prehuman and human beings, at the cost of more prolonged dependency of the infant and of the child on parental care. Separation anxiety disorder (SAD) can be seen as an exaggerated/inappropriate manifestation of SA that constitutes a gateway to poorer mental and physical health. By blending epidemiological, genetic-epidemiological, endophenotypic, and animal laboratory approaches, it is possible to delineate some of the mechanisms that link childhood-adolescence SA and SAD to health problems later in life. Causal mechanisms include gene-environment interplays and likely differential regulation of genes and functional net-works that simultaneously affect multiple behavioral and physical phenotypes after exposure to early-life adversity, including parental separation/loss.     

Neuroendocrine models of social anxiety disorder

Social anxiety disorder (SAD) is a highly prevalent and disabling disorder with key behavioral traits of social fearfulness, social avoidance, and submissiveness. Here we argue that hormonal systems play a key role in mediating social anxiety, and so may be important in SAD. Hormonal alterations, often established early in development through the interaction between biological and psychological factors (eg, genetic predisposition x early trauma), predispose to socially fearful, avoidant, and submissive behavior. However, whereas gene variants and histories of trauma persist, hormonal systems can be remodeled over the course of life. Hormones play a key role during the periods of all sensitive developmental windows (ie, prenatal, neonatal, puberty, aging), and are capable of opening up new developmental windows in adulthood. Indeed, the developmental plasticity of our social brain, and thus of social behavior in adulthood, critically depends on steroid hormones such as testosterone and peptide hormones such as oxytocin. These steroid and peptide hormones in interaction with social experiences may have potential for reprogramming the socially anxious brain. Certainly, single administrations of oxytocin and testosterone in humans reduce socially fearful, avoidant, and submissive behavior. Such work may ultimately lead to new approaches to the treatment of SAD.     

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.     

Neuroendocrine predictors of the evolution of depression

Depression is both clinically and biologically a heterogeneous entity. Despite advances in psychopharmacology, a significant proportion of depressed patients either continue to have residual symptoms or do not respond to antidepressants. It has therefore become essential to determine parameters (or predictors) that would rationalize the therapeutic choice, taking into account not only the clinical features, but also the "biological state," which is a major determinant in the antidepressant response. Such predictors can derive from bioclinical correlates and, in this context, the neuroendocrine strategy appears particularly suited. Numerous studies have investigated neuroendocrine parameters--derived mainly from dynamic challenge tests--in order to (i) determine the predictive profiles of good clinical responders to given antidepressants; (ii) monitor the progression of markers in parallel with the clinical outcome; and (iii) evaluate "in vivo" in humans the mechanisms of action of antidepressant compounds (before, during, and after treatment). This article does not attempt to be exhaustive, but rather uses selected examples to illustrate the usefulness of the investigation of the adrenal and thyroid axes and the assessment of central serotonergic, noradrenergic, and dopaminergic systems by means of neuroendocrine tests. Given methodological constraints, most of these investigations--except for baseline hormone values and the dexamethasone suppression test--cannot be used routinely in psychiatry. Despite these limitations, the neuroendocrine strategy still offers new insights in biology and the treatment of depression. Its possible expansion depends mainly on the development of specific agonists or antagonists for better investigation of the receptors supposedly involved in the pathophysiology of depression. These investigations will help define more homogeneous subgroups from a bioclinical and therapeutic viewpoint.