Neurobiology Of Anxiety Disorders Research Articles

A review of systems biology research of anxiety disorders.

The development of “omic” technologies and deep phenotyping may facilitate a systems biology approach to understanding anxiety disorders. Systems biology approaches incorporate data from multiple modalities (e.g., genomic, neuroimaging) with functional analyses (e.g., animal and tissue culture models) and mathematical modeling (e.g., machine learning) to investigate pathological biophysical networks at various scales. Here we review: i) the neurobiology of anxiety disorders; ii) how systems biology approaches have advanced this work; and iii) the clinical implications and future directions of this research. Systems biology approaches have provided an improved functional understanding of candidate biomarkers and have suggested future potential for refining the diagnosis, prognosis, and treatment of anxiety disorders. The systems biology approach for anxiety disorders is, however, in its infancy and in some instances is characterized by insufficient power and replication. The studies reviewed here represent important steps to further untangling the pathophysiology of anxiety disorders.

Neurobiology of Anxiety Disorders

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.

Neurobiology of Anxiety Disorders

In recent years, advances in the fields of neuroimaging and experimental psychology increased our understanding of the basic mechanisms of classical conditioning and learning, contributing to our knowledge of the neurobiology of anxiety disorders. Research has shown that the amygdala is the cornerstone of fear circuitry and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Activation of the amygdala in response to disorder-relevant stimuli has been observed in anxiety disorders. The roles of the hippocampus, nucleus accumbens, periaqueductal gray, and insular and medial prefrontal cortices in response to fear have been identified as well. Neurotransmitters such as serotonin, dopamine, γ-aminobutyric acid, glutamate, and some neurosteroids play an important part in the neurobiology of anxiety disorders. Neuropeptides such as oxytocin, neuropeptide Y, galanin, and cholecystokinin have been shown to modulate stress response. Drugs such as N-methyl-d-aspartate (NMDA) antagonists and blockers of voltage-gated calcium channels in the amygdala are anxiolytic. Fear extinction, which entails new learning of fear inhibition, is the mechanism of effective antianxiety treatments such as d-cycloserine, a partial NMDA agonist. Extinction is thought to occur by the medial prefrontal cortex, which inhibits the lateral amygdala under hippocampal modulation. Harnessing extinction to delink neutral stimuli from aversive responses is an important goal of the psychotherapy and pharmacotherapy of anxiety disorders. Discovery of the role of microRNAs in the etiology of anxiety disorders and their possible utility as targets to treat these disorders is fascinating. In this review, we discuss the neurobiology of anxiety disorders, which will help us better manage them clinically. This review contains 5 figures, 6 tables, and 39 references. Key words: Amygdala, anxiety disorders, neurobiology, fear conditioning, neurocircuitry, neurotransmitters, neuropeptides, neurosteroids, endogenous opioids.

Leptin polymorphism rs3828942: risk for anxiety disorders?

Leptin is an anorexigenic hormone well recognized by its role in mediating energy homeostasis. Recently, leptin has been associated with psychiatric disorders and interestingly, leptin treatment has shown antidepressant and anxiolytic effects. We examined the association of leptin levels and leptin (LEP) gene rs3828942 polymorphism with anxiety disorders considering sex differences. A cross-sectional population-based study, including 1067 young adults, of whom 291 presented anxiety disorders diagnosed by the Mini International Neuropsychiatric Interview (MINI 5.0). The rs3828942 polymorphism was genotyped by real-time PCR and ELISA measured leptin levels. Leptin levels were not associated with anxiety disorders after adjusting for sex and body mass index (BMI) [ß = - 0.009 (- 0.090-0.072); p = 0.832]. The distribution of rs3828942 genotypes was not associated with anxiety disorders. However, in a sex-stratified sample, the A-allele of rs3828942 polymorphism was associated with risk for GAD in women even when adjusting for confounding variables [OR = 1.87 (1.17-2.98); p = 0.008]. In a subsample of 202 individuals with GAD and control matched by sex and BMI, results suggest an interaction between genotypes and GAD diagnosis based on leptin levels only in the male group [F (1, 54) = 6.464; p = 0.0139]. Leptin is suggested to be related with the neurobiology of anxiety disorders in a sex-dependent manner since women carrying the A-allele of LEP rs3828942 present a higher risk for GAD, while leptin levels seem to be lower in men with GAD carrying A-allele. Studies on the relationship between leptin polymorphisms and levels are scarce and, therefore, further research is necessary.

Associations of plasma testosterone with clinical manifestations in acute panic disorder

The probable implication of testosterone in the neurobiology of anxiety disorders, and particularly panic disorder (PD), is poorly studied. We explored for potential differences concerning testosterone (T) plasma levels and the ratio testosterone/cortisol (T/C) between medication-free, consecutively-referred patients with acute exacerbation of PD comorbid with agoraphobia (PDA) (N = 40; females = 24; age = 31.4 ± 7.1 years) and healthy controls (N = 80; females = 48; matched for age). Moreover, we investigated for potential associations of T levels and T/C ratio with the severity of acute PDA psychopathology in the patients of the sample. Psychometric measures included panic attacks’ number during last three weeks (PA-21days), the Agoraphobic Cognitions Questionnaire (ACQ) and the Hamilton Anxiety Rating Scale (HARS). Male patients –but not female ones- demonstrated significantly lower T levels compared to controls. Moreover, in male patients, a significant inverse association emerged between T/C ratio and PA-21days, so that lower T/C ratio is associated with significantly more panic attacks. On the contrary, female patients demonstrated significant positive associations: (a) between T levels and PDA-related pathological cognitions (ACQ); (b) between the T/C ratio and both PA-21days and anxiety symptoms’ severity (HARS). The results of the study suggest that testosterone is significantly associated to the severity of clinical manifestations of acute panic disorder, although in a different fashion concerning the two genders.

Glucocorticoid administration restores salience network activity in patients with spider phobia.

Glucocorticoids reduce phobic fear in patients with anxiety disorders. Although the neurobiology of anxiety disorders is not fully understood, convergent structural and functional neuroimaging studies have identified abnormalities in various brain regions, including those in the salience network (SN) and default mode network (DMN). Here, we examine the effects of glucocorticoid administration on SN and DMN activity during the processing of phobic stimuli. We use functional magnetic resonance imaging to record brain activity in 24 female patients with spider phobia who were administered either 20mg of cortisol or placebo while viewing pictures of spiders. Fourteen healthy female participants were tested with the same task but without substance administration. Independent component analysis (ICA) performed during stimulus encoding identified the SN and DMN as exhibiting synchronized activation in diverse brain regions; thus, we examined the effects of cortisol on these networks. Furthermore, participants had to rate their level of fear at various time points. Glucocorticoids reduced phobic fear in patients with spider phobia. The ICA performed during stimulus encoding revealed that activity in the SN and DMN was reduced in placebo-treated patients versus healthy controls. Brain activity in the SN, but not the DMN, was altered in cortisol- versus placebo-treated patients to a level that was similar to that observed in healthy controls. Activity in both the SN and DMN was reduced in patients with spider phobia. Cortisol administration altered the SN activity to a level that was comparable to that found in healthy controls. This alteration in SN activity might reflect the fear-reducing effects of glucocorticoids in phobia.

Assessment and treatment of anxiety disorders in children and adolescents.

Recent advances in the developmental epidemiology, neurobiology, and treatment of pediatric anxiety disorders have increased our understanding of these conditions and herald improved outcomes for affected children and adolescents. This article reviews the current epidemiology, longitudinal trajectory, and neurobiology of anxiety disorders in youth. Additionally, we summarize the current evidence for both psychotherapeutic and psychopharmacologic treatments of fear-based anxiety disorders (e.g., generalized, social, and separation anxiety disorders) in children and adolescents. Current data suggest that these disorders begin in childhood and adolescence, exhibit homotypic continuity, and increase the risk of secondary anxiety and mood disorders. Psychopharmacologic trials involving selective serotonin reuptake inhibitors (SSRIs) and selective serotonin norepinephrine reuptake inhibitors (SSNRIs) are effective in pediatric patients with anxiety disorders and have generally demonstrated moderate effect sizes. Additionally, current data support cognitive behavioral therapy (CBT) for the treatment of these conditions in youth and suggest that the combination of psychotherapy + an SSRI may be associated with greater improvement than would be expected with either treatment as monotherapy.

Anxiety and Separation Disorders

• Based on strong research evidence, anxiety disorders are the most common psychiatric illness in children and adolescents. • Based on some research evidence, the neurobiology of anxiety disorders is linked to dysregulation in the fear and stress response system in the brain. • Based on strong research evidence, separation anxiety disorder is one of the most common causes of school refusal, and addressing both the function of the behavior and returning to school as soon as possible is recommended. (7)• Based on strong research evidence, CBT is the first-line treatment for anxiety disorders in children and adolescents. • Based on strong research evidence, SSRIs are effective for treatment of moderate-to-severe anxiety disorders in children and adolescents.

Elucidation of neurobiology of anxiety disorders in children through pharmacological challenge tests and cortisol measurements: a systematic review

Anxiety disorders are common both in adults and children. While there have been major advances in understanding the neurobiology of anxiety disorders in adults, progress has been more limited in the elucidation of the mechanisms underlying these disorders in childhood. There is a need to delineate childhood biological models, since anxiety represents a significant clinical problem in children and is a risk factor for the subsequent development of anxiety and depression in adulthood. We conducted a review of the literature regarding pharmacological challenge tests and direct hypothalamic-pituitary-adrenal axis measurement in children with anxiety disorders, with emphasis on panic disorder and social anxiety disorder. Studies identified were contrasted with those in adult panic disorder and social anxiety disorder. Despite this broad approach few studies emerged in children, with only 22 studies meeting inclusion criteria. When contrasted with adult neurobiological models of panic disorder and social anxiety disorder, children studied showed some abnormalities which mirrored those reported in adults, such as altered baseline respiration, altered responses to CO(2) challenge tests and blunted growth hormone response to yohimbine. However, results differed from adults with panic disorder and social anxiety in some aspects of noradrenergic and serotonergic function. For endpoints studied in panic disorder children, unlike adults, displayed a lack of baseline end-tidal CO(2) abnormalities and a different hypothalamic-pituitary-adrenal pattern response under low-dose CO(2). The biology of these anxiety disorders in children may only partially mirror that of adult anxiety disorders. However, caution is required as the evidence is limited, and many studies combined patients with panic disorder and social anxiety disorder with other disorders or non-specific anxiety. Further research is required to fully understand the biology and progression of childhood anxiety disorders.

The American Psychiatric Publishing textbook of psychopharmacology

Part I: Principles of Psychopharmacology. Neurotransmitters, receptors, signal transduction, and second messengers in psychiatric disorders. Basic principles of molecular biology and genomics. Chemical neuroanatomy of the primate brain. Electrophysiology. Animal models. Psychoneuroendocrinology. Principles of pharmacokinetics and pharmacodynamics. Brain-immune system interactions: relevance to the pathophysiology and treatment of neuropsychiatric disorders. Brain imaging in psychopharmacology. Statistics and clinical trial design in psychopharmacology. Pharmacoeconomics. Part II: Classes of Psychiatric Treatments: animal and human pharmacology. Antidepressants and Anxiolytics. Tricyclic and tetracyclic drugs. Fluoxetine. Sertraline. Paroxetine. Fluvoxamine. Citalopram and s-citalopram. Monoamine oxidase inhibitors. Trazodone and nefazodone. Bupropion. Mirtazapine. Venlafaxine. Duloxetine and milnacipran. Benzodiazepines. Buspirone and gepirone. Investigational treatments for mood and anxiety disorders: CRH receptor antagonists, NK-1 receptor antagonists, and glucocorticoid receptor antagonists. Antipsychotics. Classic antipsychotic medications. Clozapine. Olanzapine. Quetiapine. Aripiprazole. Risperidone. Ziprasidone. Drugs to treat extrapyramidal side effects. Drugs for Treatment of Bipolar Disorder. Lithium. Valproate. Carbamazepine and oxcarbazepine. Gabapentin. Lamotrigine. Topiramate. Other Agents. Cognitive enhancers. Sedative-hypnotics. Psychostimulants in psychiatry: amphetamine, methylphenidate, and modafinil. Electroconvulsive therapy. Part III: Clinical Psychobiology and Psychiatric Syndromes. Biology of mood disorders. Neurobiology of schizophrenia. Neurobiology of anxiety disorders. Biology of Alzheimer's disease. Neurobiology of substance abuse disorders. Biology of eating disorders. Biology of personality disorders. Part IV: Psychopharmacological Treatment. Treatment of depression. Treatment of bipolar disorder. Treatment of schizophrenia. Treatment of anxiety disorders. Management of noncognitive symptoms of dementia: behavioral and psychological symptoms of dementia. Treatment of childhood and adolescent disorders. Treatment of substance-related disorders. Treatment of eating disorders. Treatment of agitation and aggression in the elderly. Treatment of personality disorders. Psychiatric emergencies. Treatment during late life. Psychopharmacology during pregnancy and lactation. Treatment of insomnia. Index.

Recent advances in the neurobiology of anxiety disorders: Implications for novel therapeutics

Anxiety disorders are a highly prevalent and disabling class of psychiatric disorders. This review focuses on new directions in neurobiological research and implications for the development of novel psychopharmacological treatments. Neuroanatomical and neuroimaging research in anxiety disorders has centered on the role of the amygdala, reciprocal connections between the amygdala and the prefrontal cortex, and, most recently, alterations in interoceptive processing by the anterior insula. Anxiety disorders are characterized by alterations in a diverse range of neurochemical systems, suggesting ample novel targets for drug therapies. Corticotropin-releasing factor (CRF) concentrations are elevated in a subset of anxiety disorders, which suggests the potential utility of CRF receptor antagonists. Pharmacological blockade of the memory-enhancing effects of stress hormones such as glucocorticoids and noradrenaline holds promise as a preventative approach for trauma-related anxiety. The glutamatergic system has been largely overlooked as a potential pharmacological target, although convergent preclinical, neuroimaging, and early clinical findings suggest that glutamate receptor antagonists may have potent anxiolytic effects. Glutamatergic receptor agonists (e.g., D-cycloserine) also have an emerging role in the treatment of anxiety as facilitators of fear extinction during concurrent behavioral interventions. The neuropeptides substance P, neuropeptide Y, oxytocin, orexin, and galanin are each implicated in anxiety pathways, and neuropeptide analogs or antagonists show early promise as anxiolytics in preclinical and/or clinical research. Each of these active areas of research holds promise for expanding and improving evidence-based treatment options for individuals suffering with clinical anxiety.

The neurobiology of anxiety in children and adolescents

Summary There have been a number of advances in the understanding of the neurobiology of anxiety disorders in recent years. Most of these advances have involved the study of adults, but advances have also been made in the understanding of pathologic anxiety in children. This article reviews the anatomy of normal fear and pathologic anxiety. In addition, developmental and temperamental predisposition to anxiety is also reviewed. Finally, the neurobiology of specific anxiety disorders is reviewed including data from the study of children and adults.

Neurobiology of anxiety disorders: Focus on neuroimaging

Traumatic brain injury (TBI) can precipitate new-onset psychiatric symptoms or worsen existing psychiatric conditions. To elucidate specific mechanisms for this interaction, neuroimaging is often used to study both psychiatric conditions and TBI. This systematic review aims to synthesize the existing literature of neuroimaging findings among patients with anxiety after TBI.We conducted a Preferred Reporting Items for Systematic Review and Meta-Analyses–compliant literature search via PubMed (MEDLINE), PsychINFO, EMBASE, and Scopus databases before May, 2019. We included studies that clearly defined TBI, measured syndromal anxiety as a primary outcome, and statistically analyzed the relationship between neuroimaging findings and anxiety symptoms.A total of 5982 articles were retrieved from the systematic search, of which 65 studied anxiety and 13 met eligibility criteria. These studies were published between 2004 and 2017, collectively analyzing 764 participants comprised of 470 patients with TBI and 294 non-TBI controls. Imaging modalities used included magnetic resonance imaging, functional magnetic resonance imaging, diffusion tensor imaging, electroencephalogram, magnetic resonance spectrometry, and magnetoencephalography. Eight of 13 studies presented at least one significant finding and together reflect a complex set of changes that lead to anxiety in the setting of TBI. The left cingulate gyrus in particular was found to be significant in 2 studies using different imaging modalities. Two studies also revealed perturbances in functional connectivity within the default mode network.This is the first systemic review of neuroimaging changes associated with anxiety after TBI, which implicated multiple brain structures and circuits, such as the default mode network. Future research with consistent, rigorous measurements of TBI and syndromal anxiety, as well as attention to control groups, previous TBIs, and time interval between TBI and neuroimaging, are warranted. By understanding neuroimaging correlates of psychiatric symptoms, this work could inform future post-TBI screening and surveillance, preventative efforts, and early interventions to improve neuropsychiatric outcomes.

Agents in Development for Anxiety Disorders

Benzodiazepines have been used as anxiolytics for many years, despite well described withdrawal effects and drug interactions. Serotonergic antidepressants, which benefit from a favourable adverse effect profile and do not cause dependence, are now established first-line treatments for anxiety disorders. It is apparent, however, that current treatments are not ideal, particularly as they do not always produce a complete recovery. Our growing knowledge of the neurobiology of anxiety disorders, aided by advances in neuroimaging and pharmacological challenges, has led to the development of other potential anxiolytics. Agents with increased specificity for serotonin receptor subtypes have been developed, with the aim of maximising therapeutic efficacy while minimising adverse effects. Novel anxiolytics, such as neuropeptide agonists and antagonists, γ-aminobutyric acid (GABA)A receptor partial agonists, N-methyl-D-aspartate (NMDA) receptor antagonists, neurosteroids and others, are currently in development and may eventually offer alternatives to currently available agents.

The neurobiology of anxiety disorders

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The Neurobiology of Anxiety Disorders

The use of pharmacologic challenges and the application of new brain imaging technologies in the study of patients with anxiety disorders have led to an improvement in the understanding of the neurobiologic basis of these disorders. Abnormal function of noradrenergic, serotonergic, GABAergic, and dopaminergic neural systems as well as abnormal chemoreceptor reactivity have all been implicated in the pathophysiology of anxiety. Functional imaging data have revealed abnormal patterns of cortical and subcortical activity in anxiety patients. These data have allowed significant improvements in the available anatomic models of the anxiety disorders. Further improvements in research technique and technology likely will lead in the near future to a significantly clearer image of the neurobiologic processes involved in anxiety disorders.

Neurobiology of Anxiety Disorders

Most neurobiologic studies conducted in humans with anxiety disorders have been either in adults with panic disorder or in adults and children with obsessive-compulsive disorder. The author reviews what is known about the neurobiology of anxiety in adults, and neurobiologic correlates of animal models of anxiety.