Neurobiology Of Panic Disorder Research Articles

Arousal and the attentional network in panic disorder.

Although a great deal of information about the neurobiology of panic disorder is now available, there is a need for an updated etiological model integrating recent findings on the neurobiology of the arousal system and its relationship with higher cortical functions in panic disorder. The current mini-review presents psychophysiological, molecular biological/genetic and functional neuroimaging evidence for dysfunction in major arousal systems of the brain. Such dysfunction may influence the development of panic disorder by precipitating autonomic bodily symptoms and at the same time increasing vigilance to these sensations by modulating cortical attentional networks. A multilevel model of arousal, attention and anxiety-including the norepinephrine, orexin, neuropeptide S and caffeine-related adenosine systems-may be useful in integrating a range of data available on the pathogenesis of panic disorder.

Emotional Reactivity and Regulation in Panic Disorder: Insights from a Functional Magnetic Resonance Imaging Study of Cognitive Behavioral Therapy

l i r t a P H p n U s p t s e c i t F or more than a century, psychologists and psychiatrists have sought to understand the biological bases of mental disorders, with a view to fashioning more effective treatments. Advances in functional neuroimaging have made it possible for clinical researchers to make significant strides towards realizing this long-held goal, allowing them to do the following: 1) characterize differences in neural responses between patients with various psychiatric conditions and healthy subjects (HS), and 2) examine the neural correlates of psychosocial and biologic treatments. One particular target of investigation has been the anxiety disorders, which constitute the most common family of psychiatric disorders, with a lifetime prevalence of 28.8% (1). Compared with HS, patients with anxiety disorders demonstrate hyperactivity in the insula and amygdala, key regions in the fear network (2,3). In addition to shared features, there are important differences among anxiety disorders. For example, hypoactivation in the rostral anterior cingulate cortex (ACC), dorsal ACC, ventromedial prefrontal cortex (PFC), and thalamus is more characteristic of posttraumatic stress disorder than social anxiety disorder (SAD) or specific phobias (2). In contrast, hyperactivation in the amygdalae and insular cortex is found more frequently in SAD and specific phobias than in posttraumatic stress disorder (2). Related research examining the neural correlates of psychosocial treatments for anxiety disorders has found that cognitive behavioral therapy (CBT) decreases blood flow to the amygdala and the medial temporal lobe in patients with SAD during an anxiety-inducing task (4). Research in patients with specific phobias has demonstrated that CBT leads to reduced activation in the anterior insula and increased activation in the dorsolateral PFC (4). These findings suggest that the neural mechanisms underlying anxiety may be specific to each disorder and that the mechanisms associated with change during CBT may be disorder specific as well. Despite the wealth of research examining the neural correlates of anxiety disorders, surprisingly little is known about the neurobiology of panic disorder (PD). Panic disorder is marked by internally generated threat, vegetative symptoms, and sudden extreme anxiety (3). Maladaptive associative learning is thought to play a role in the etiology of PD, and research has shown that patients with PD extrapolate learned fears to related stimuli (5). Agoraphobia (the avoidance of situations in which escape or assistance may not be possible) commonly co-occurs with panic disorder (PD/A) (6). The neural correlates of PD/A are not well described, but one positron emission tomography study found that, compared with HS, PD/A patients displayed higher levels of glucose uptake in the bilateral amygdala, hippocampus, and thalamus (among other regions) (7), providing evidence for the role of the fear network in PD/A. Only two studies have investigated the neural correlates of CBT for PD/A,

Dopamine transporter binding in females with panic disorder may vary with clinical status

Background To date the involvement of dopamine system in neurobiology of panic disorder (PD) has been not investigated by imaging studies in humans. In this study, we evaluated the binding potential of dopamine transporter (DAT) in striatum of patients with PD. Methods Subjects comprised seven female patients with current PD, seven female PD patients in remission and seven female healthy controls, matched by age. Striatal DAT binding was evaluated using single-photon emission computed tomography and [ 123I]nor-β-CIT tracer. Results Significantly higher DAT binding in striatum was detected in remitted PD females as compared with both currently ill PD and control females. The females with current PD demonstrated non-significant lowering in striatal DAT binding as compared with healthy controls. The correlation analysis in total sample of female patients showed significant and inverse relationship between striatal DAT binding characteristics and severity of panic symptoms. Conclusions This is first report showing that DAT binding in striatum may depend on the clinical status in females with PD. Our data suggest that increased level of DAT may contribute to stability of remission; however, the exact involvement of dopamine system in PD pathogenesis requires further investigations. The preliminary results of current study should be confirmed by other independent studies and should also be extended to include male patients.

Panic Disorder: Is the PAG Involved?

Data from studies with humans have suggested that abnormalities of midbrain structures, including the periaqueductal gray matter (PAG), could be involved in the neurobiology of panic disorder (PD). The electrical stimulation of the PAG in neurosurgical patients induces panic-like symptoms and the effect of drugs that are effective in the treatment of PD in the simulation of public speaking model of anxiety is in agreement with data from animal models of PD. Structural neuroimaging studies have shown increases in gray matter volume of midbrain and pons of PD patients. There is also evidence of lower serotonin transporter and receptor binding, and increases of metabolism in the midbrain of PD patients. Nevertheless, these midbrain abnormalities can not be considered as specific findings, since neuroimaging data indicate that PD patients have abnormalities in other brain structures that process fear and anxiety.

The Neurobiology of Panic Disorder: Toward an Integrated Model

AbstractPanic disorder (PD) is a complex, multidimensional psychiatric disorder characterized by the presence of panic attacks as well as anticipatory anxiety and panic-related phobias (eg, agoraphobia). Although the etiology of this disabling disorder remains unclear, advances in basic neuroscience and in imaging studies have led to a greater understanding of the neurocircuitry and neurochemistry that are involved in modulating fear and anxiety and that are relevant to understanding PD. A preliminary integrated model can be outlined, but there is a need for additional research that cuts across genetic investigation, provocation studies, neuroimaging techniques, and treatment trials. As research continues and greater insight into the mechanisms underlying PD is achieved, additional treatment strategies may emerge.

Serotonin Function in Panic Disorder: Important, But Why?

The essential role of serotonin (5-hydroxytryptamine (5-HT)) system in the neurobiology and pharmacotherapy of panic disorder (PD) continues to be a topic of intensive interdisciplinary research. Interest in the involvement of 5-HT in PD has been fuelled by clinical studies demonstrating that medications increasing the synaptic availability of 5-HT, such as selective 5-HT re-uptake inhibitors, are effective in the treatment of PD. Rival theories of 5-HT deficiency vs excess have attempted to explain the impact of 5-HT function in PD. In the past decade, knowledge of the role of 5-HT in the neurobiology of PD has expanded dramatically due to much new research including experimental, treatment, brain-imaging, and genetic studies. The current review attempts to summarize the new data and their implications. The challenge and treatment studies generally confirm the specific inhibitory influence of 5-HT on panicogenesis. The brain-imaging studies in PD patients demonstrate functional and clinically relevant alterations in various elements of 5-HT system affecting the neurocircuitry of panic. The findings of genetic association studies suggest that certain 5-HT-related genes may contribute to the susceptibility to PD; however, these data are rather limited and inconsistent. It appears that, even if not the primary etiological factor in PD, the 5-HT function conveys important vulnerability, as well as adaptive factors. A better understanding of these processes may be critical in achieving progress in the treatment of patients suffering from PD.

Reduced brain serotonin transporter binding in patients with panic disorder

There is strong evidence for the importance of the serotonin (5-HT) system in the neurobiology of panic disorder (PD); however, the exact role of this system remains unclear. The 5-HT transporter (5-HTT) is a key element in 5-HT neurotransmission. The current study aimed to investigate the binding of 5-HTT in the brain of patients with PD. We used single-photon emission computed tomography with a radioligand that specifically labels the 5-HTT, [ 123I]nor-β-CIT. Subjects comprised eight patients with current PD, eight patients with PD in remission, and eight healthy control subjects. The patients with current PD showed a significant decrease in 5-HTT binding in the midbrain, in the temporal lobes and in the thalamus in comparison to the controls. The binding of 5-HTT in patients with PD in remission was similar to findings in the control group in the midbrain and in the temporal lobes, but lower in the thalamus. Regional 5-HTT binding significantly and negatively correlated with the severity of panic symptoms. These findings point to a dysregulation of the 5-HT system in PD patients. Altered function of 5-HTT appears to be related to the clinical status of patients. Clinical improvement in the patients in remission is associated with normalization of 5-HTT binding.

Cholecystokinin and panic disorder.

Evidence for implication of cholecystokinin (CCK) in the neurobiology of panic disorder is reviewed through animal and human pharmacological studies. The results of these investigations raise two issues: (i) selectivity of action of CCK-2 agonists in anxiety disorders; and (ii) aberrations of the CCK system in anxiety disorders, both of which are discussed.

The role of serotonin in panic: evidence from tryptophan depletion studies.

There has been growing interest in the role of serotonin (5-hydroxytryptamine, 5-HT) in anxiety, including pathological states such as panic disorder. The technique of tryptophan depletion (TD), which causes an acute, temporary and reversible reduction in brain 5-HT levels, is a useful minimally invasive paradigm to aid the research of the role of 5-HT in various disorders. This review discusses the evidence supporting the hypothesis that 5-HT function is of importance in the neurobiology of panic disorder and considers in more detail how our understanding has been influenced by work using the technique of TD. Possible avenues for future research are also discussed.

Association of cholecystokinin‐A receptor gene polymorphisms and panic disorder in Japanese

Several lines of evidence have suggested that naturally occurring alterations in cholecystokinin (CCK) systems could contribute to the development of panic disorder (PD). Among recent investigations, polymorphisms of the CCK and CCK-B receptor (R) genes were investigated, but the results were inconclusive. We recently cloned the genomic structures of human CCK-AR, and determined the transcriptional start site of the human CCK-AR gene. Two sequence changes were detected in the promoter region: a G to T change in nucleotide -128 and an A to G change in nucleotide -81 (GenBank database under accession number D85606). The frequencies of the genotypes and haplotypes of these two polymorphisms were compared in 109 Japanese patients with PD and 400 age- and gender-matched normal Japanese control subjects. The frequency of variant genotypes (-81A/G, -128G/T; G/G, G/T, and G/G, T/T) having variant haplotype (-81G/-128T) was significantly higher in PD than in controls (P < 0.0001, OR = 2.81, 95% CI = 1.74-4.39). The statistical differences between the haplotype distributions in the PD and control groups were highly significant: the frequency of variant haplotype (-81G/-128T) was higher in the former group than in the latter (P < 0.0001). This association was not affected by clinical characteristics such as age, gender, and age at onset of PD. In this study, the first to report the positive association of the CCK-AR polymorphisms and PD, haplotype analyses further strengthened the association based on our comparison of genotype distributions. The CCK-AR gene polymorphism may be involved in the neurobiology of PD.

Acute and Chronic Role of 5-HT3 Neuronal System on Behavioral and Neuroendocrine Changes Induced by Intravenous Cholecystokinin Tetrapeptide Administration in Humans

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (Δmax) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, Δmax for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Effects of Cholecystokinin Tetrapeptide on Respiratory Function in Healthy Volunteers

The authors evaluated respiratory response to cholecystokinin tetrapeptide (CCK-4) in healthy volunteers. Subjects were randomly assigned to either a CCK-4 (N = 15) or placebo (N = 15) challenge under double-blind conditions. Dyspnea was reported by all of the subjects who received CCK-4 but only one subject who received placebo. CCK-4 caused a significant increase in tidal volume and minute ventilation but had no effect on breathing frequency. Placebo had no effect on any of the respiratory measures. These data indicate that the behavioral effects of CCK-4 are accompanied by changes in respiration in healthy volunteers.

Neurobiology of panic disorder

Neurobiology of panic disorder

The role of the 'central' cholecystokinin-B receptor in panic disorder.

Research investigating the neurobiological underpinnings of anxiety disorder have mainly been focused on dysfunction of the GABA, noradrenergic and serotonergic (5-HT) neuronal systems. Just recently, in both animal and human studies, evidence has been found for a possible role of the cholecystokinin (CCK) neuronal system in the pathogenesis of anxiety disorder. Behaviorally, animal studies revealed anxiogenic-like properties for the 'central' CCKB receptor agonists, while CCKB receptor antagonists displayed intrinsic anxiolytic properties. Similarly, in man, CCKB receptor agonists, like pentagastrin and CCK4, were found to be able to elicited panic attacks in both panic disorder (PD) patients and healthy volunteers. These effects appear due to stimulation of the CCKB receptor. In addition, clinically effective panicolytic agents reduce the sensitivity to CCK4 in PD patients. Taken together, these findings may suggest a role for CCK in the neurobiology of PD. On the other hand, there is circumstantial evidence for involvement of several other neuronal systems, such as the serotonergic, noradrenergic and GABA-ergic system, in the regulation of anxiety. Interestingly, evidence has been found for an interaction between CCK and 5-HT and that this interaction plays a role in the mediation of anxiety. This presentation will critically discuss the evidence for the role of the CCKB receptor in anxiety and in addition, will focus on the putative evidence that the role of CCK in anxiety is mediated by its interaction with the serotonergic neuronal system.

Anxiogenic effects of m-CPP in patients with panic disorder: Comparison to caffeine's anxiogenic effects

The behavioral and neuroendocrine effects of meta-chlorophenylpiperazine ( m-CPP), a serotonergic agonist, were compared with the effects of caffeine, an adenosine antagonist, in panic disorder patients. Patients with panic disorder were given single oral doses of 0.5 mg/kg m-CPP, 480 mg caffeine, and placebo on separate days under double-blind conditions. Both m-CPP and caffeine had significantly greater anxiogenic and panic-inducing effects than placebo, although caffeine produced nonsignificantly greater increases on all anxiety rating scales than m-CPP. Both m-CPP and caffeine produced significant equivalent increases in plasma cortisol concentrations, but only m-CPP produced plasma prolactin increases. These findings provide further evidence implicating both the serotonergic and adenosinergic receptor systems in the neurobiology of panic disorder.

Review of Neurobiology of Panic Disorder.

Review of Neurobiology of Panic Disorder.

NEUROBIOLOGY OF PANIC DISORDER: FRONTIERS OF CLINICAL NEUROSCIENCE. Volume 8. 1990. Edited By James C. Ballenger. Published by John Wiley &amp; Sons, Inc., New York. 391 pages. $109 Cdn. approx.

NEUROBIOLOGY OF PANIC DISORDER: FRONTIERS OF CLINICAL NEUROSCIENCE. Volume 8. 1990. Edited By James C. Ballenger. Published by John Wiley &amp; Sons, Inc., New York. 391 pages. $109 Cdn. approx. - Volume 18 Issue 1