The Neurobiology of Panic: A Chronic Stress Disorder.
ABSTRACT: Panic disorder is an often chronic and impairing human anxiety syndrome, which frequently results in serious psychiatric and medical comorbidities. Although, to date, there have been many advances in the diagnosis and treatment of panic disorder, its pathophysiology still remains to be elucidated. In this review, recent evidence for a neurobiological basis of panic disorder is reviewed with particular attention to risk factors such as genetic vulnerability, chronic stress, and temperament. In addition, neuroimaging data are reviewed which provides support for the concept of panic disorder as a fear network disorder. The potential impact of the National Institute of Mental Health Research Domain Criteria constructs of acute and chronic threats responses and their implications for the neurobiology of panic disorder are also discussed.
Project description:Panic disorder is one of the chronic and disabling anxiety disorders. There has been evidence for either genetic heterogeneity or complex inheritance, with environmental factor interactions and multiple single genes, in panic disorder's etiology. Linkage studies have implicated several chromosomal regions, but no research has replicated evidence for major genes involved in panic disorder. Researchers have suggested several neurotransmitter systems are related to panic disorder. However, to date no candidate gene association studies have established specific loci. Recently, researchers have emphasized genome-wide association studies. Results of two genome-wide association studies on panic disorder failed to show significant associations. Evidence exists for differences regarding gender and ethnicity in panic disorder. Increasing evidence suggests genes underlying panic disorder overlap, transcending current diagnostic boundaries. In addition, an anxious temperament and anxiety-related personality traits may represent intermediate phenotypes that predispose to panic disorder. Future research should focus on broad phenotypes, defined by comorbidity or intermediate phenotypes. Genome-wide association studies in large samples, studies of gene-gene and gene-environment interactions, and pharmacogenetic studies are needed.
Project description:Anxious depression is a common, distinct clinical subtype of major depressive disorder (MDD). This review summarizes current neurobiological knowledge regarding anxious depression. Peer-reviewed articles, published January 1970 through September 2012, were identified via PUBMED, EMBASE, and Cochrane Library, using the following key words: anxious depression electroencephalography (EEG), anxious depression functional magnetic resonance imaging (fMRI), anxious depression genetics, anxious depression neurobiology, and anxious melancholia neurobiology. Despite a general dearth of neurobiological research, the results suggest that anxious depression-when defined either syndromally or dimensionally-has distinct neurobiological findings that separate it from nonanxious depression. Structural neuroimaging, EEG, genetics, and neuropsychiatric studies revealed differences in subjects with anxious depression compared to other groups. Endocrine differences between individuals with anxious depression and those with nonanxious depression have also been noted, as evidenced by abnormal responses elicited by exogenous stimulation of the system. Despite these findings, heterogeneity in the definition of anxious depression complicates the results. Because exploring the neurobiology of this depressive subtype is important for improving diagnosis, prognosis, and treatment, enrichment strategies to decrease heterogeneity within the field should be employed for future research.
Project description:Panic disorder is characterized by symptoms with abrupt surges of fear with palpitations, sweating, trembling, heat sensations. Considering its disease burden on each individual and on society, understanding its etiology is important. Though no one specific etiology has been known, like other psychiatric disorders, multiple factors such as genetic, environmental, neurobiological, psychopathological factors have been suggested. In this article, we reviewed currently known etiologies and related study results, regarding especially genetic and epigenetic aspects of the panic disorder. Early studies, including twin studies, family studies, adoption studies suggested highly familial trait of panic disorder. Linkage studies, either, found panic disorder is not a single gene disorder but confirmed existence of multiple related genes. Chromosome and candidate gene studies found few related genes, NPY, ADORA2A, COMT, IKBKE. Newer method, genome-wide association studies (GWAS) have been searching for newer genes. No genome-wide significant genes, however, were detected, confirming previously known candidate genes, NPY5R on 4q31.3-32, BDKRB2 on 14q32, instead. Epigenetic modification has also been studied on many different psychiatric disorders. Monoamine oxidase A (MAOA) hypomethylation, taken together with negative life events, showed relation with panic disorder. Glutamate decarbodylases 1 (GAD1) hypomethylation was also specific on panic disorder patients. Relation with noradrenaline transporter (NET) gene SLC6a2 promoter methylation has also been studied. In conclusion, no specific gene or epigenetic pattern can fully explain etiology of panic disorder. Few genes and epigenetic patterns, however, showed strong association with panic disorder compared to healthy controls. Considering its multivariable background, further studies with larger populations can confirm current results and clarify etiologies of panic disorder.
Project description:The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.
Project description:Panic disorder is a severe anxiety disorder with recurrent, debilitating panic attacks. In individuals with panic disorder there is evidence of decreased central gamma-aminobutyric acid (GABA) activity as well as marked increases in autonomic and respiratory responses after intravenous infusions of hypertonic sodium lactate. In a rat model of panic disorder, chronic inhibition of GABA synthesis in the dorsomedial-perifornical hypothalamus of rats produces anxiety-like states and a similar vulnerability to sodium lactate-induced cardioexcitatory responses. The dorsomedial-perifornical hypothalamus is enriched in neurons containing orexin (ORX, also known as hypocretin), which have a crucial role in arousal, vigilance and central autonomic mobilization, all of which are key components of panic. Here we show that activation of ORX-synthesizing neurons is necessary for developing a panic-prone state in the rat panic model, and either silencing of the hypothalamic gene encoding ORX (Hcrt) with RNAi or systemic ORX-1 receptor antagonists blocks the panic responses. Moreover, we show that human subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. Taken together, our results suggest that the ORX system may be involved in the pathophysiology of panic anxiety and that ORX antagonists constitute a potential new treatment strategy for panic disorder.
Project description:Although the neurobiological mechanisms underlying panic disorder (PD) are not yet clearly understood, increasing amount of evidence from animal and human studies suggests that the amygdala, which plays a pivotal role in neural network of fear and anxiety, has an important role in the pathogenesis of PD. This article aims to (1) review the findings of structural, chemical, and functional neuroimaging studies on PD, (2) relate the amygdala to panic attacks and PD development, (3) discuss the possible causes of amygdalar abnormalities in PD, (4) and suggest directions for future research.
Project description:Objectives:Previous research on alexithymia has led to controversy over its prevalence in panic disorder. The aim of this study was to assess the difference in the prevalence of alexithymia in panic disorder and other anxiety disorders. Design and Methods:We performed a cross-sectional study on a sample of 71 patients diagnosed with panic disorder and 113 patients diagnosed with other anxiety disorders; both groups were 18-50 years old. Primary outcome was the 20-item Toronto Alexithymia Scale (TAS) score. Secondary outcome was the prevalence of alexithymia defined as a TAS score ?61. Results:Patients diagnosed with panic disorder had a 25% higher score on the TAS subscale of difficulty identifying feelings than patients diagnosed with other anxiety disorders. The prevalence of alexithymia was 27% in patients with panic disorder and 13% in patients with other anxiety disorders. Patients diagnosed with panic disorder had significantly higher odds for alexithymia. Conclusions:The results of our study support the hypothesis of higher prevalence of alexithymia in individuals with panic disorder than in individuals with other anxiety disorders. In addition, difficulty identifying feelings as a salient feature of alexithymia is higher in panic disorder than in other anxiety disorders.
Project description:Panic disorder with or without agoraphobia is a commonly occurring disorder affecting 2 to 3% of the population in Sweden. Untreated, panic disorder is a chronic condition that significantly increases the risk for psychiatric comorbidity, morbidity and mortality, employment difficulties, and healthcare utilization. Cognitive behavioral approaches are the recommended first-line treatment for panic disorder; however, many patients in routine care receive another evidence-based psychotherapy, including psychodynamic therapy. Allowing patients to choose among evidence-based approaches to panic disorder may improve outcomes and reduce overall health costs. Trials comparing the 'gold standard' treatment for panic disorder to other evidence-based psychotherapies are needed, and also trials that can separate patient preferences for treatment from randomization effects on outcome, disability and healthcare utilization in the longer term.A phase 2/3 doubly-randomized controlled trial carried out in routine care with 216 adults (aged 18 to 70 years) with a primary diagnosis of DSM-IV Panic Disorder (with or without Agoraphobia). Within each clinic, patients are randomized to self-selection, random assignment of treatment, or wait-list. Patients choose or are randomly assigned to either Panic Control Treatment or Panic-Focused Psychodynamic Psychotherapy. Primary outcomes are changes in panic symptom severity, occupational status, and sickness-related absences from work at post-treatment and 6, 12 and 24 months post-treatment. Secondary outcomes include changes in agoraphobic avoidance, psychiatric comorbidity, disability, and healthcare utilization. The study also employs elements of an effectiveness trial as therapist and service-related effects on outcome will be estimated. Putative change mechanisms for the two treatments are also assessed.Cognitive behavioral and psychodynamic therapies are both evidence-based approaches that are routinely offered to panic disordered patients in Sweden. However, little is known about the relative effectiveness of these two approaches for panic/agoraphobia, work-related disability and healthcare utilization over the longer term. The current trial (POSE) also addresses the important but understudied issue of whether patient preference for a particular psychotherapeutic approach moderates outcome.ClinicalTrials.gov NCT01606592 (registered 19 March 2012).
Project description:<h4>Introduction</h4>Panic-like anxiety (panic attacks with or without panic disorder), a highly treatable condition, is the most prevalent condition associated with unexplained chest pain in the emergency department. Panic-like anxiety may be responsible for a significant portion of the negative consequences of unexplained chest pain, such as functional limitations and chronicity. However, more than 92% of panic-like anxiety cases remain undiagnosed at the time of discharge from the emergency department. The 4-item Panic Screening Score (PSS) questionnaire was derived in order to increase the identification of panic-like anxiety in emergency department patients with unexplained chest pain.<h4>Methods and analysis</h4>The goals of this prospective cohort study were to (1) refine the PSS; (2) validate the revised version of the PSS; (3) measure the reliability of the revised version of the PSS and (4) assess the acceptability of the instrument among emergency physicians. Eligible and consenting patients will be administered the PSS in a large emergency department. Patients will be contacted by phone for administration of the criterion standard for panic attacks as well as by a standardised interview to collect information for other predictors of panic attacks. Multivariate analysis will be used to refine the PSS. The new version will be prospectively validated in an independent sample and inter-rater agreement will be assessed in 10% of cases. The screening instrument acceptability will be assessed with the Ottawa Acceptability of Decision Rules Instrument.<h4>Ethics and dissemination</h4>This study protocol has been reviewed and approved by the Alphonse-Desjardins research ethics committee. The results of the study will be presented in scientific conferences and published in peer-reviewed scientific journals. Further dissemination via workshops and a dedicated website is planned.
Project description:Panic disorder (PD) is one of the most common psychiatric disorders. Recurrent, unexpected panic attacks (PAs) are the primary symptom and strongly impact patients' quality of life. Clinical manifestations are very heterogeneous between patients, emphasizing the need for a dimensional classification integrating various aspects of neurobiological and psychological circuits in line with the Research Domain Criteria (RDoC) proposed by the US National Institute of Mental Health. To go beyond data that can be collected in the daily clinical situation, experimental panic provocation is widely used, which has led to important insights into involved brain regions and systems. Genetic variants can determine the sensitivity to experimental models such as carbon dioxide (CO2) exposure and can increase the risk to develop PD. Recent developments now allow to better assess the dynamic course of PAs outside the laboratory in patients' natural environment. This can provide novel insights into the underlying mechanisms and the influence of environmental factors that can alter gene regulation by changing DNA methylation. In this mini review, we discuss assessment of PAs in the clinic, in the laboratory using CO2 exposure, genetic associations, and the benefits of real-life assessment and epigenetic research.