Psychological Co-morbidity in Functional Gastrointestinal Disorders: Epidemiology, Mechanisms and Management

Functional gastrointestinal disorder (FGID) is one of the commonest digestive diseases worldwide and leads to significant morbidity and burden on healthcare resource. The putative bio-psycho-social pathophysiological model for FGID underscores the importance of psychological distress in the pathogenesis of FGID. Concomitant psychological disorders, notably anxiety and depressive disorders, are strongly associated with FGID and these psychological co-morbidities correlate with severity of FGID symptoms. Early life adversity such as sexual and physical abuse is more commonly reported in patients with FGID. There is mounting evidence showing that psychological disorders are commonly associated with abnormal central processing of visceral noxious stimuli. The possible causal link between psychological disorders and FGID involves functional abnormalities in various components of the brain-gut axis, which include hypothalamic-pituitary-adrenal system, sympathetic and parasympathetic nervous system, serotonergic and endocannabinoid systems. Moreover, recent studies have also shown that psychological distress may alter the systemic and gut immunity, which is increasingly recognized as a pathophysiologic feature of FGID. Psychotropic agent, in particular antidepressant, and psychological intervention such as cognitive behavioral therapy and meditation have been reported to be effective for alleviation of gastrointestinal symptoms and quality of life in FGID patients. Further studies are needed to evaluate the impact of early detection and management of co-morbid psychological disorders on the long-term clinical outcome and disease course of FGID

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence

Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis

Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders

Mental disorders including depression and anxiety are continuously rising their prevalence across the globe. Early-life experience of individuals emerges as a main risk factor contributing to the developmental vulnerability to psychiatric disorders. That is, perturbing environmental conditions during neurodevelopmental stages can have detrimental effects on adult mood and emotional responses. However, the possible maladaptive neural mechanisms contributing to such psychopathological phenomenon still remain poorly understood. In this review, we explore preclinical rodent models of developmental vulnerability to psychiatric disorders, focusing on the impact of early-life environmental perturbations on behavioral aspects relevant to stress-related and psychiatric disorders. We limit our analysis to well-established models in which alterations in the serotonin (5-HT) system appear to have a crucial role in the pathophysiological mechanisms. We analyze long-term behavioral outcomes produced by early-life exposures to stress and psychotropic drugs such as the selective 5-HT reuptake inhibitor (SSRI) antidepressants or the anticonvulsant valproic acid (VPA). We perform a comparative analysis, identifying differences and commonalities in the behavioral effects produced in these models. Furthermore, this review discusses recent advances on neurodevelopmental substrates engaged in these behavioral effects, emphasizing the possible existence of maladaptive mechanisms that could be shared by the different models.Fil: Adjimann, Tamara Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Argañaraz, Carla Veronica. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Soiza Reilly, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Identifying the mechanisms of antidepressant drug action in mice lacking brain serotonin

Serotonin gilt als Hauptangriffsstelle gängiger Antidepressiva bei schweren Depressionen, wie bspw. selektive Serotonin-Wiederaufnahmehemmer (SSRI), und -Enhancer (SSRE). Es bleibt offen, ob SSRI / E ausschließlich über die Manipulation des Serotoninspiegels wirken, oder ob alternative Signalwege daran beteiligt sind. Ansatzpunkte hierfür sind beispielsweise die neurotrophen Signalwege (spez. Brain derived neurotophic factor, BDNF) oder die Hypothalamus-Hypophysen-Nebennieren- (HPA) – Signalwege des Stressachsensystems. Ebenfalls wurde in Nagetiermodellen beobachtet, dass mit der Dysregulation des zentralen Serotoninsystems bei schweren Depressionen, ein Rückgang der Neurogenese im Gyrus dentatus des Hippocampus einhergeht. Ziel dieser Arbeit war, das Zusammenspiel von Serotonin, BDNF, adulter Neurogenese und der Stressachse zu untersuchen. Zentrum der Studien ist ein Mausmodell, mit einer genetischen Depletion des zentralen Serotonin-synthetisierenden Enzyms Tryptophanhydroxylase 2 (sog. Tph2-/- Mäuse). Es wurden die physiologische Reaktionen auf die Behandlung mit gängigen Antidepressiva abhängig von der Abwesenheit von Serotonin untersucht, um mögliche alternative Signalwege aufzeigen zu können. Die bekannte Zunahme der Neurogenese nach SSRI/SSRE-Behandlung wurde in Wildtyptieren beobachtet, während die Therapie in Tph2-/- Mäusen keine direkte kausale Wirkung zeigte. Im Gegensatz dazu waren die BDNF-Spiegel in depressionsrelevanten Hirnregionen in Tph2-/- Mäusen nach SSRI, signifikant verringert. Auch zeigen die Studien eine neurobiologische Relevanz von Serotonin im ZNS, bei den antidepressiven Mechanismen einer Elektrokonvulsiven Krampftherapie. Ebenfalls deuten erhöhte Neurogeneseraten bei lebenslanger Abwesenheit von Serotonin im ZNS, Therapiemethoden-unabhängig, möglicherweise auf eine modulierte Stressreaktion hin. Untersuchungen der Parameter des HPA-Stressachsensystems, wiesen auf einen grundlegend veränderten Stresshormonspiegel in Tph2-/- Mäusen hin.Serotonin, the "molecule of happiness" is an important target for antidepressants. The mainly prescribed drugs in major depression are selective serotonin re-uptake inhibitors (SSRI); but recently, SSR-enhancer (SSRE) have also attracted clinical attention. However, only a quarter of patients responds to treatment. It needs to be determined, whether SSRI/E act solely via manipulating serotonin levels or whether other pathways are involved, e.g. neurotrophic signaling (brain-derived neurotrophic factor, BDNF) or the hypothalamus-pituitary-adrenal (HPA)-axis. Furthermore, in major depression, dysregulation of central serotonin signaling is accompanied with a decline in hippocampal neurogenesis, as has been observed in rodent models. At the center of this thesis is a mouse model deficient in the central serotonin-synthesizing enzyme, tryptophan hydroxylase 2 (Tph2-/- mice). I have investigated physiological responses to antidepressant treatment in the absence of brain serotonin, and the possible role of alternative pathways. I observed the typical increase in neurogenesis upon SSRI treatment in WT mice, while it had no effect in Tph2-/- mice. In contrast, BDNF levels were significantly decreased in Tph2-/- mice after treatment with no effect in WT control mice. Furthermore, my results show a critical role of brain serotonin in the neurobiological effects of electroconvulsive seizure. Surprisingly, in animals lacking central serotonin, increased neurogenesis was observed independently of the treatment. The gathered data indicated an altered stress response; therefore, parameters of the HPA-axis have been studied, indicating a downregulated HPA system in Tph2-/-animals in baseline state, but showed no difference in treatment or feedback control. This thesis gives insight into the mechanisms of antidepressant action and reveals ideas for novel pathways involved in the process that could be used as targets in therapeutic approaches and further research in major depression

Testing antidepressant compounds in a neuropsychological model of drug action

Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental medicine models have been proposed as preclinical tools in order to predict drug efficacy before the stage large RCTs. Among the various experimental medicine models, the cognitive neuropsychological model has been proposed as a tool to predict the efficacy of antidepressant drug even before the stage of large scale and expensive RCTs. We applied the cognitive neuropsychological model of drug action to test antidepressant effects of a novel compound (ARA290) and a well-known compound (L-tryptophan). We further investigated the model by tapping into HPA-axis reactivity and social decision making as additional outcomes, and investigated their interaction with a genetic marker.VICI grant (NWO) - Prof. dr. Willem van der DoesUBL - phd migration 201

cGMP Signaling, Phosphodiesterases and Major Depressive Disorder

Deficits in neuroplasticity are hypothesized to underlie the pathophysiology of major depressive disorder (MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic transmission and neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerable attention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosine monophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade is also expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. Cyclic GMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effector molecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degrade cGMP into 5’GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review a growing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvement in MDD and antidepressant action

Treatment failure in major depression associated with chronic inflammation of the immune system : a psychoneuroimmunological hypothesis

The pharmacological treatment of major depressive disorder (MDD) fails to respond in 30%-50% of the cases, triggering researchers to dig deeper into the neurobiological underpinnings of depression. This has put the immune system in the spotlight and induced the formulation of the "cytokine hypothesis of depression". The current literature demonstrates an association between antidepressant action and cytokine function in MDD, suggesting that the lack of clinical benefit of antidepressants is, somehow, associated with the activation of the inflammatory system. We suggest a new treatment approach merging pharmacological and behavioral pre-anti-inflammatory treatment to reduce the chronic inflammation of the immune systemEl tractament farmacològic per trastorn depressiu major (TDM) presenta un fracàs en el 30%-50% dels casos, impulsant als investigadors a investigar a fons les bases neurobiològiques de la depressió. Això ha posat al sistema immunològic en el punt de mira i ha induït a la formulació de la hipòtesis de la depressió provocada per citoquines. La literatura científica actual demostra una associació entre l'acció dels antidepressius i la funció de les citoquines en TDM, suggerint que l'activació del sistema immunològic d'alguna manera afecten a als poc beneficis dels antidepressiu. Suggerim un nou apropament al tractament que integri tractament farmacològic i no farmacològic pre-anti-inflamatòri per reduir la inflamació crònica del sistema immunològi

An investigation of neurochemical, structural and functional characteristics in the murine model of collagen induced arthritis

Depression and rheumatoid arthritis have an estimated co-morbidity of 13-20%. However, the mechanisms whereby peripheral inflammation might alter brain function are unknown. We hypothesised that pro-inflammatory cytokines released in the periphery will result in neurochemical, structural and functional changes related to depression. Therefore, the aim of this thesis was to investigate altered central nervous system function in a rodent model of rheumatoid arthritis, the murine model of collagen induced arthritis (CIA). The CIA model is an established model used to investigate novel anti-inflammatory agents and resembles rheumatoid arthritis as the model is chronic and involves an autoimmune response to type II collagen. To our knowledge brain function in the CIA model has not previously been examined. Therefore, we began by identifying key neurochemical, cellular and functional changes associated with depression which had the greatest likelihood of being influenced by pro-inflammatory cytokines. Serotonin and dopamine transporter densities. The serotonergic system is implicated in the pathology of depression and there is evidence that pro-inflammatory cytokines may influence the serotonin transporter (SERT) in vitro. In vitro autoradiography binding of [125I]-β-carbomethoxy-3-β-(4 iodophenyl)tropane ([125I]-β-CIT) in the presence of mazindol and [3H]-citalopram was used to determine SERT binding in mice with CIA and controls. Out of 15 regions of interest investigated a significant change in SERT binding was identified by [125I]-β-CIT binding, in the nucleus accumbens (58%), thalamus (62%), and dentate gyrus (-60%) in CIA mice compared to controls. However, no significant difference in SERT density was detected in any region by [3H]-citalopram binding. Dopamine transporter (DAT) binding sites were also examined using [125I]-βCIT in the presence of displacer fluoxetine and [3H]-WIN 35,428. Out of 14 regions investigated a significant difference in DAT binding was only observed in the caudate putamen (95%) in the CIA group in comparison to the control group. However, no significant difference in DAT binding was detected in any region by [3H]-WIN 35,428 binding. A limitation of this study was the small group sizes and the degree of clinical symptoms in the CIA group. The data suggest that SERT and DAT transporter densities are not altered by CIA. [14C]-2-Deoxyglucose autoradiographic study of local cerebral glucose utilisation. To investigate brain function the [14C]-2-deoxyglucose ([14C]-2-DG) autoradiographic technique and a challenge to the serotonergic system were employed to identify any abnormalities in regional cerebral glucose utilisation. Overall there was no significant difference in the index of cerebral glucose utilization (iLCMRglu) in mice with chronic clinical symptoms of CIA. To investigate altered serotonergic function in the CIA model fenfluramine, a drug which stimulates serotonin release and blocks serotonin re-uptake was employed. Fenfluramine challenge in the CIA group resulted in only 3 out of the 35 regions of interest examined being significantly different from fenfluramine challenged controls. The orbital cortex (-41%) and the molecular level of the hippocampus (-26%) demonstrated a significant difference in iLCMRglu Overall the data suggest minimal influence of CIA on brain function. Cell proliferation and cell survival in the hippocampus. Hippocampal atrophy is implicated in the pathology of depression and there is evidence to suggest that pro-inflammatory cytokines reduce cell proliferation in vitro. To investigate hippocampal cell proliferation mice were administered 5’ –bromo-2’-deoxyuridine (BrdU), a marker of proliferating cells, prior to and after developing chronic clinical symptoms of CIA. There was no significant difference in cell proliferation prior to the development of clinical symptoms. There was a statistically significant increase in cell proliferation after chronic clinical symptoms in the CIA model in one out of two separate experiments. The data has been interpreted cautiously due to the fact the significant increase in cell proliferation was not reproduced. Cell survival was also investigated during the onset of clinical symptoms and the data demonstrated no significant effect of CIA on cell survival. Conclusion. The data indicate minimal influence of peripheral inflammation on the central nervous system, at least in the murine CIA model. Two possible explanations are that the CIA murine model is not a suitable model to detect changes in brain function associated with rheumatoid arthritis or that uninvestigated neurochemical systems play a role. This thesis highlights our limited understanding of the CIA model and whether or not it represents the features associated with rheumatoid arthritis other then peripheral inflammation. Further characterisation of the brain and development of the CIA model is required to establish if it is a suitable model to investigate the association between depression and rheumatoid arthritis. This is important as understanding the cause of depression and how the cause influences the brain will allow for the development of more specific treatments