Current Pharmaceutical Design - Volume 18, Issue 35, 2012

Symptom provocation has proved its worth for understanding the pathophysiology of diseases and in general for the development of new therapeutic approaches in the medical field. In the research of anxiety disorders, investigations using experimentally induced panic attacks by various agents, such as sodium lactate, carbon dioxide, cholezystokinine-tetrapetid etc., have a long tradition and allow the exploration of usually naturally occuring spontaneous psychopathological phenomena under controlled conditions. Post-Traumatic Stress Disorder (PTSD) is a prevalent disorder that can develop following exposure to an extreme traumatic event. In DSM-IV it is currently classified as an anxiety disorder and shares phenomenological similarities with panic disorder. The use of panicogenic challenge tests is also an interesting neurobiological approach to learn more about the nature of PTSD and may be a possibility to develop new therapeutic strategies for the treatment of PTSD symptoms. Not only panic anxiety, but also flashbacks and other dissociative symptoms can be provoked by several panicogens in PTSD. The purpose of this review is to evaluate studies using panicogens in PTSD. Methodological short-comings of current studies and needed directions of further research are discussed.

Background: The validity of experimentally induced panic attacks as a model to study the pathophysiology of panic disorder has been questioned. Unspecific, unpleasant and aversive effects as well as specific patterns of psychovegetative symptoms pointing to different subtypes of panic disorder patients have been observed. These findings raise the question of challenge paradigms as a valuable tool to identify different vulnerabilities in patients with panic disorder. Methods: We compared the two most widely studied panicogenic drugs sodium lactate and cholecystokinine tetrapeptide (CCK-4) with placebo in 25 patients with panic disorder and matched healthy control subjects. Psychophysiological changes were measured using the Acute Panic Inventory (API) and visual analogue scales for anxiety and arousal. Results: In patients with panic disorder 18 out of 25 experienced a sodium lactate- or a CCK-4 induced panic attack. Lactate or CCK-4 induced symptoms and induced panic attacks were only correlated in healthy controls, but not in patients with panic disorder. Conclusion: The mechanisms of lactate and CCK-4 induced panic attacks are distinct in panic disorder patients but not in healthy controls. Different neurobiological vulnerabilities may be uncovered by different challenges.

It has been well established that the inhalation of Carbon Dioxide (CO2) can induce in humans an emotion closely replicating spontaneous panic attacks, as defined by current psychiatry nosology. The purpose of this review is to provide a critical summary of the data regarding CO2's psychopharmacological properties and underlying mechanisms. The authors review the literature on the human and animal response for the exposure of exogenous CO2 focusing on five points of interest: 1) the early history of the use of CO2 as an anesthetic and therapeutic agent, 2) the subjective effects of breathing CO2 at different concentrations in humans, 3) the use of CO2 in experimental psychiatric research as an experimental model of panic, 4) the pharmacological modulation of CO2-induced responses, and 5) the putative neurobiological mechanisms underlying the affective state induced by CO2. The authors conclude with an evolutionary-inspired notion that CO2 might act as an agent of a primal emotion serving a homeostatic function, in the control of respiration and acid-base balance.

Visual emotional stimulation is supposed to elicit psycho-vegetative reactions, which are similar to as the ones elicited by exposure to actual experience. Visual stimulation paradigms have been widely used in studies on agoraphobia with and without panic disorder. However, the applied imagery has hardly ever been disorder- and subject- specific. 51 patients with an ICD-10 and DSM-IV diagnosis of agoraphobia with or without panic disorder (PDA) and matching healthy controls have been examined. Subjects were confronted with 146 picture showing characteristic agoraphobic situations (high places, narrow places, crowds, public transport facilities, or wide places) or pictures associated with acute physical emergency (panic) situations, which had been pre-selected by anxiety experts. Participants were asked to rate emotional arousal induced by the respective images on the Self- Assessment Manikin scale (SAM). Data on PDA severity (PAS) depressive symptoms (MADRS) and sociodemographic data were recorded. Saliva cortisol levels were measured before and after exposure in a second test applying the individually mostly feared stimuli combined with emotionally neutral pictures for every single patient. 117 of the PDA-specific images were rated significantly more fear-eliciting by patients than by healthy individuals. Sub-categorization into agoraphobia clusters showed differential effects of clusters with regard to gender distribution, severity of PDA and cortisol secretion during exposure. In this study disorder specific and individual characteristics of agoraphobia were assessed for use in future trials applying emotional imagery. It could be used for the differential assessment of PDA and associated neurobiological and psychological phenomena and in neuroimaging paradigms.

Posttraumatic stress disorder (PTSD) is a common condition for which existing treatments are ineffective for many patients. Recent discoveries in the neurobiology of learning and memory, along with expanding knowledge of how those systems are impacted by the biology of the stress response, have opened new arenas for potential medication treatments for PTSD. We conducted a review of registered clinical trials investigating the efficacy of new agents for PTSD. The glucocoritcoid and adrenergic signaling systems are the most frequent targets of these investigational approaches to the prevention and treatment of PTSD. Additional trials are evaluating modulation of other CNS targets, including neurosteroids, glutamate, gamma-amino butyric acid, endocannabinoids, oxytocin, neurokinin/Substance P, and dopamine. A particularly exciting area of research is studies examining Medication-Enhanced Psychotherapy (MEP). Medications provided before or after exposure therapy for PTSD can enhance outcomes by: 1) strengthening learning and memory of fear extinction; 2) disrupting reconsolidation, thereby weakening fear memories; or 3) facilitating engagement in psychotherapy by reducing fear and enhancing openness to experience. The next few years promise to produce insight into the neurobiology and clinical efficacy of several novel approaches in the pharmacologic treatment and prevention of PTSD.

Cognitive behavioral therapy (CBT) has been shown to be an effective intervention for anxiety disorders. However, despite its proven efficacy, some patients fail to respond to an adequate course of treatment. In attempts to improve the efficacy of CBT, researchers have augmented the core learning processes of the intervention with d-cycloserine (DCS), an N-Methyl-D-Aspartate partial agonist. This article reviews the current literature on DCS as an augmentation strategy for CBT for anxiety disorders. We will describe the memory enhancing properties of DCS, review findings from randomized controlled studies of DCS in anxious populations and discuss mechanism, dosing and timing issues.

Stressful life events and dysfunctional Hypothalamic Pituitary Adrenal (HPA) axis have been implicated in the pathogenesis of psychiatric disorders, including anxiety disorders. This paper attempts to review the existing literature on childhood traumata, recent life events, HPA axis functioning and their relationship in Post-Traumatic Stress Disorder, Panic Disorder, Generalized Anxiety Disorder, Obsessive Compulsive Disorder and Social Phobia. Preclinical and clinical models will be analyzed. Stressful life events seem to have a role in the onset and in the course of these disorders and HPA axis abnormalities have been reported in almost all anxiety disorders. The hypothesis that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology, will be evaluated.

Panic disorder is a frequent and disabling mental disorder characterized by recurrent periods or abrupt surges of intense fear or discomfort, the panic attacks. The clinical phenomenology of panic attacks suggests a prominent role of a disturbed stress response regulation in the aetiopathology of this disorder. We summarize the results of challenge tests of the hypothalamus-pituitary-adrenocortical (HPA) axis in panic disorder and give an overview of studies using psychosocial challenge paradigms. The results of HPA axis challenge tests suggest an increased expression of the hypothalamic neuropeptides, but an intact negative feedback inhibition at the level of the pituitary. Psychosocial challenge tests give evidence for dissociation between the subjective stress response and the HPA axis response in panic disorder, which might be the result of an over-focussed self-monitoring leading to an enhanced stress perception despite normal HPA axis activation. We integrated these findings in a cognitive stress control model suggesting that panic disorder patients develop efficient strategies to control the somatic stress response despite a hypothalamic hyperdrive of the HPA axis. To employ these strategies at the right time, patients acquired an enhanced perception of stress symptoms, leading to the reported dissociation of the subjective and HPA axis response. It can be inferred from these findings that cognitive behavioral therapy addressing over-focussed self-monitoring and maladaptive control strategies in combination with pharmacological treatment against over-expression of the hypothalamic neuropeptides should be an effective treatment in severe forms of panic disorder, which corresponds with recent treatment guidelines.

Background: Panic disorder (PD) has a strong genetic component showing high heritability rates and familial aggregation. Moreover, there is evidence for associations between parental PD and patterns of psychopathology. So far, little is known about possible endophenotypes representing premorbid vulnerability markers in high-risk subjects for PD. In the present study, we investigated saccadic eye movement (SEM) as an index of CNS inhibitory function in subjects at high risk for PD. Methods: 132 healthy children at high and low familial risk for PD were included in the study. Basal SEM parameters were obtained using an electro-oculography (EOG) based system measuring peak saccadic eye velocity (pSEV), latency and accuracy. Moreover, with regard to self rating scales, state-trait-anxiety (STAI-C), childhood behavioral inhibition (CSRI), and anxiety sensitivity (CASI) were assessed. Results: There was a significant overall difference for basal SEM parameters across groups as revealed by MANCOVA (F7,118=2.184, p=.040). A significant influence was found for the covariate age, while gender and puberty status had no influence on SEM. High-risk (HR) subjects showed significantly lower pSEV. Moreover, levels of state and trait anxiety were higher in HR children (F1=5.429, p=.021). Discussion: In our sample, measurement of pSEV allowed discrimination between children at high and low risk for PD. Since these results argue for possible alterations of saccadic function in high risk subjects, differences in underlying neurobiological mechanisms might be discussed as a possible endophenotype of PD.

Clinical genetic studies propose a strong genetic contribution to the pathogenesis of anxiety disorders with a heritability of about 30-67%. The present review will give an overview of linkage studies, association studies and genome-wide association studies (GWAS) yielding support for some candidate genes. Additionally, first evidence for gene-environment interactions between candidate genes of anxiety disorders and stressful life events will be reported. On a systems level, neural activation correlates of anxiety-relevant emotional processing and neurophysiological measures such as peripheral sympathetic activity or the startle reflex have been shown to be potentially driven by vulnerability genes of anxiety disorders. Promising current approaches to further dissect the genetic underpinnings of anxiety disorders such as next generation sequencing, epigenetic analyses and pharmaco-/ psychotherapy-genetics will be presented. Genetic research in anxiety disorders will be discussed with respect to its potential benefit for future efforts to develop innovative and individually tailored therapeutic approaches for patients with anxiety disorders.

A large body of research including animal and human studies has confirmed the crucial role of the serotonin (5-HT) system in the regulation of anxiety-related behaviour and traits. In the past decade, the functional status of the 5-HT system in anxiety disorders has been regularly investigated by novel neuroimaging techniques, such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Although these studies shed more light on several aspects of the 5-HT functioning in patients with anxiety disorders, the current knowledge about the specific role of the 5-HT system in particular anxiety phenotypes remains fragmentary. In this paper, we review the available data from SPECT and PET imaging studies of the 5-HT system in anxiety disorders, attempt to dissect the involvement of the 5-HT in neural circuits of anxiety and discuss some issues that need to be considered for further research in this area.

In addition to the classical neurotransmitters, neuropeptides represent an important class of modulators for affective behaviors and associated disorders, such as anxiety disorders. Many neuropeptides are abundantly expressed in brain regions involved in emotional processing and anxiety behaviors. Moreover, risk factors for anxiety disorders such as stress modulate the expression of various neuropeptides in the brain. Due to the high prevalence of anxiety disorders and yet limited treatment options, there is a clear need for more effective therapeutics. In this regard, the various neuropeptides represent exciting candidates for new therapeutic designs. In this review, I will provide an up-to-date summary on the evidences for the involvement of seven neuropeptides in anxiety: corticotropin-releasing factor, urocortins, vasopressin, oxytocin, substance P, neuropeptide Y and galanin. This review will cover the behavioral effects of these neuropeptides in animal models of anxiety by both genetic and pharmacological manipulations. Human studies indicating a role for these neuropeptides in anxiety disorders will also be discussed.

Inflammatory and autoimmune diseases are classically considered as disorders arising from hyper-activation of immunity and hence are treated with drugs that suppress the lymphocyte activation and inflammation. Although this strategy has proven useful to cure symptoms, it rarely can heal the disease and long-term treatments are usually needed. Inflammatory and autoimmune diseases frequently occur also in patients with primary immune deficiency disease, proving that immune hyper-activation may paradoxically arise from defective function of immune genes. In these cases, the phenotype of hyper-activation is believed to reflect the attempts of the immune system to compensate for immune defects. Recent data suggest that similar mechanisms could be involved also in the pathogenesis of some multifactorial disorders, such as Crohn's disease and systemic lupus erythematosus. Based on these considerations, novel therapies could be developed to cure severe autoimmune and inflammatory disorders, not only by aiming to hyper-activation but as well by focusing on the possible underlying immune defects.

The inflammatory response is of major importance in host defence, but is involved in all acute and chronic diseases. Multiple inflammatory cells and molecules are involved. Among the latter, the Nuclear Factor -κB (NF-κB) has been found to be most important and present in all cell types. NF-B regulates the expression of a large number of genes involved in inflammation. NF-κB plays a key role in the orchestration of the multifaceted inflammatory response, not only in the first pro-inflammatory phase, but also later in the regulation of the resolution of inflammation, when anti-inflammatory genes are expressed and apoptosis is induced. The review describes NF-κB and its two pathways: the canonical, mediated by the p65 and p50 subunits, and the non-canonical, mediated by the subunits RelB, p52 and p50. The relevance of the kinases and interactions leading to NF-κB activation is considered in different primary cells (i.e. macrophages, dendritic cells, fibroblasts, cells from inflammatory tissues), together with the response induced and the ligand involved. Then we overview the different steps to NF-B activation that can be targeted (IKKs, IκBα or NF-κB subunits themselves) with various technologies available i.e. small molecules peptides or nucleic acids. A rationale is provided for possible targets to consider, in the light that NF-κB signaling pathways regulates both pro-inflammatory and anti-inflammatory responses. The possibility of using NF-κB targeted dendritic cells in immunotherapy is considered.

Inflammation is a highly regulated process involved both in the response to pathogens as well as in tissue homeostasis. In recent years, a complex network of proteins in charge of inflammation control has been revealed by the study of hereditary periodic fever syndromes. Most of these proteins belong to a few families and share the capability of sensing pathogen-associated and damageassociated molecular patterns. By interacting with each other, these proteins participate in the assembly of molecular platforms, called inflammasomes, which ultimately lead to the activation of cytokines, to the transcription of inflammatory genes or to the induction of cell apoptosis. Among hereditary periodic fever syndromes, mevalonate kinase deficiency (MKD) is the sole in which the phenotype did not directly associate with a deficiency of these proteins, but with a metabolic defect of the mevalonate pathway, highlighting the importance of this metabolic pathway in the inflammation control. Noteworthy, drugs acting on this pathway can greatly influence the inflammatory response. The modulation of inflammation by mevalonate pathway is of interest, since it may involve mechanisms not directly referable to inflammasomes. MKD provides a model to study these mechanisms and possibly to develop new classes of anti-inflammatory drugs.

Celiac disease is a multi-systemic autoimmune disease of the small bowel induced by gluten in genetically predisposed subjects. Highly specific and gluten-dependent production of auto-antibodies targeting self-proteins of the transglutaminase family occurs in the intestinal mucosa. These anti-transglutaminase antibodies are found deposited in intestinal and extra-intestinal tissue where they might exert biological effects, together with the intestinal mucosal gliadin-specific T lymphocytes. We conducted a brief review on antitransglutaminase antibodies effects, discussing their roles in the pathogenesis of several clinical manifestations of celiac disease.

Type 1 diabetes mellitus (T1DM) is an autoimmune disease, due to the immune-mediated destruction of pancreatic β-cells, whose incidence has been steadily increasing during the last decades. Insulin replacement therapy can treat T1DM, which, however, is still associated with substantial morbidity and mortality. For this reason, great effort is being put into developing strategies that could eventually prevent and/or cure this disease. These strategies are mainly focused on blocking the immune system from attacking β-cells together with functional islet restoration either by regeneration or transplantation. Recent experimental evidences suggest that TNFrelated apoptosis-inducing ligand (TRAIL), which is an immune system modulator protein, could represent an interesting candidate for the cure for T1DM and/or its complications. Here we review the evidences on the potential role of TRAIL in the management of T1DM.

Pediatric inflammatory and autoimmune diseases are a wide array of systemic or organ-specific conditions, characterized by an exaggerated immune reactivity, which generally occurs in immunogenetically predisposed children. Among the most important ones, in terms of their diffusion and morbidity in the population worldwide, pediatric inflammatory bowel disease (IBD) and juvenile rheumatoid arthritis (JRA) have to be considered. The aim of personalized therapy is to give to each patient the most appropriate drug and dose regimen, in order to maximize treatment response and reduce the risk of adverse events. In general, several therapeutic options exist for pediatric inflammatory and autoimmune conditions, therefore the perspective of pharmacological tools that allow identification of patients with increased risk of treatment issues related to a particular medication, in terms of lack of efficacy or increased probability of adverse events, is particularly desirable and promising. The present review will be focused on the personalized therapy approaches already available or in development for pediatric patients with IBD or JRA, comprising pharmacokinetic, pharmacodynamic and pharmacogenetic assays.