Modern trends in pharmacopsychiatry最新文献

In the translation of psychoneuroimmunology research into clinical practice, one critical step is to identify biomarkers for improved diagnosis and targeting of interventions. Inflammatory markers deserve special attention due to their crucial role linking various health conditions and disorders. In this chapter, we discuss the pivotal roles of cytokines in signalling to the brain and leading to behavioural changes. This is followed by a review of recent research findings into neuroimmunology of depression, and immunomodulating effects of antidepressants. The rest of the chapter focuses on neuroinflammatory hypothesis in anxiety disorders, and provides an overview of current research evidence on inflammatory responses in anxious state and anxiety disorders. Research suggestions are recommended, including study design, risk factors, medication effects, and measurement strategies. Clinical and pharmacotherapeutic implications and future research directions are also discussed in the final section.

Evidence suggests that inflammation, an innate immune response facilitating recovery from injury and pathogenic invasion, is positively associated with age-related cognitive decline and may play a role in risk for dementia. Physiological pathways linking the peripheral immune and central nervous systems are outlined, and studies linking inflammation with neurocognitive function are overviewed. We also present recent studies from our laboratory showing that midlife inflammation is related to cognitive function and brain morphology. Finally, potential implications for treatment, future directions, and limitations are discussed.

Neuroinflammation is used to describe an immune-related process that occurs within the central nervous system (CNS). The objective of this chapter is to introduce basic aspects of neuroinflammation in the context of psychiatric disorders. Inflammatory processes are evident in the CNS with a myriad of stimuli including neurological disease, CNS injury or infection, peripheral infection, and psychological stress. Because the CNS maintains a degree of immune privilege, endothelial cells of the blood-brain barrier (BBB) and resident CNS innate immune cells are integral to the interpretation and propagation of inflammatory signals. For instance, activated CNS immune cells and the BBB coordinate production of cytokines and secondary messengers that act directly to influence neurophysiology. Another key concept is that there is bidirectional communication between the immune system and CNS. Afferent neuro-immune pathways relay the peripheral inflammatory profile to the CNS by secretion of cytokines and direct neuronal activation. Communication through afferent neuro-immune pathways promotes physiological and behavioral responses that are aimed to help clear pathogens from the host. For example, peripheral infection increases circulating IL-1β that induces production of prostaglandins and IL-1β by CNS immune cells that initiate fever and the behavioral symptoms of sickness. Although transient cytokine responses in the brain may be beneficial to the host, prolonged neuroinflammation associated with chronic illness, neurodegenerative disease, stress, and aging impair neuroimmune regulation and negatively affect normal cognitive and behavioral processes. Thus, understanding neuroimmune regulation and mechanisms that mediate neuroinflammation is important because these pathways likely contribute to the pathophysiology of several mental health disorders.

Advances in the basic neuroscience of fear conditioning and extinction, as well as in the clinical neuroscience of posttraumatic stress disorder (PTSD), have laid the foundations for research on the pharmacotherapy of PTSD. Clinical trials have ranged from early work on tricyclic antidepressants and benzodiazepines through to more recently introduced antidepressants, and on to a range of other psychotropic agents. Despite the growing database of trials, the area remains a controversial one insofar as key systematic reviews in the field have emphasized the methodological limitations of existing work. Here, we briefly review the existing literature on the pharmacotherapy of PTSD, attempting to highlight key clinical lessons, and important areas for future research.

Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue (CF) are distinct diagnostic categories with regard to clinical symptoms, severity of illness and biomarkers. Patients with ME and CFS show higher scores on fatigue, neurocognitive disorders, hyperalgesia, autonomic symptoms, postexertional malaise and a subjective feeling of infection than patients with CF. ME is characterized by increased postexertional malaise, a subjective feeling of infection and neurocognitive disorders and is a more severe variant than CFS. Fukuda's 1994 CDC criteria are adequate to make a distinction between patients with ME/CFS and CF, while ME/CFS patients should be subdivided into those with and without postexertional malaise into ME and CFS, respectively. Different interrelated pathophysiological mechanisms play a role in ME/CFS, i.e. (1) inflammation and immune activation, (2) oxidative and nitrosative stress and lowered antioxidant defenses, (3) activation of cell signaling networks, e.g. nuclear factor ĸβ, the 2 9 ,5 9 -oligoadenylate/RNase-L and/or protein kinase R pathway, (4) a transition towards autoimmune reactions, and (5) bacterial translocation. The inflammatory biomarkers are higher in ME/CFS than in CF and higher in ME than in CFS. The above-mentioned pathways may explain the onset of characteristic ME/CFS symptoms, such as fatigue, malaise, autonomic symptoms, hyperalgesia, and neurocognitive symptoms. Different etiological factors may trigger ME/CFS/CF, e.g. viral and bacterial infections, and (auto)immune and inflammatory disorders, while psychosocial and physical stressors act as modulating factors. New pathophysiologically driven drug candidates for ME and CFS are discussed which target the pathways that play a role in ME/CFS.

Both glucocorticoids and inflammation have been implicated in the pathogenesis of depression. There is a large body of literature indicating that hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid receptor (GR) dysfunction are present in a significant proportion of depressed patients. There is also evidence of increased inflammatory processes in depressed populations, with higher levels of cytokines being a prominent finding - including raised levels of IL-6, and IL-1. These findings appear difficult to reconcile given the well-recognised property of glucocorticoids as prominent anti-inflammatory molecules. There are three potential solutions posed to this dilemma. Firstly, it has been argued that the glucocorticoid system and the inflammatory system exist in balance with one another and chronic stress can disrupt this balance in favour of inflammatory processes at the expense of glucocorticoid signalling. It has also been suggested that glucocorticoids have more complex actions than typically thought, and, in low levels can actually be pro-inflammatory, rather than universally anti-inflammatory. Lastly, it is possible that inflammation and glucocorticoid signalling may act on the same processes and structures without direct interaction to give rise to cumulative damage. Improved understanding of this interaction will allow further progress in determining targets for treatment.

The 'early intervention' model has been applied with good results to the care of a range of serious medical conditions. The key rationale for this model is to guarantee early identification and treatment for the illness, thus preventing its progression to a more advanced and severe stage. It would also provide a framework for optimal treatment according to the stage of the disorders. Although in the field of psychiatry this model has mainly been implemented in nonaffective psychosis, research evidence supports its application in other mental disorders. To promote this initiative, the chapter explores the available evidence demonstrating the feasibility of adopting the key elements of the model in the care of the whole spectrum of anxiety disorders. In addition, the chapter describes the different stages that are possible to identify in the process of developing an illness, and also the phase-specific interventions that could be applied. Finally, the service repercussions of implementing an early intervention model in anxiety disorders are discussed.

Obsessive-compulsive disorder (OCD) and related disorders are costly and burdensome long-term illnesses. Whilst evidence-based pharmacological and psychological treatments are available for OCD, a significant proportion of OCD patients fail to respond and for many of the OCD-related disorders no validated treatments are as yet recognised. In addition, predictors of treatment response/non-response to guide clinicians in the management of individual patients are lacking. The introduction of personalised medicine to psychiatry is expected to offer the novel prospect of identifying the most effective treatment for a patient in a timely and cost-effective way. Translational research that investigates endophenotype predictors of treatment response in OCD and related disorders may pave the way toward personalised medicine. Such research is likely to require multidisciplinary collaboration between neuroscientists and clinicians, so that the right clinical questions are addressed, and large datasets, entailing multinational, multicentre sampling. In order to facilitate the translational investigation of the key aspects of the treatment response, these studies would require access to standardised treatment paradigms that are internationally recognised. In this chapter, we introduce some of the most important outstanding questions for personalised medicine that translational research could be expected to address within the next 10 years. We review the available tools and techniques for standardised clinical assessment and the criteria that are used to define the degree of therapeutic response (response, remission, relapse, resistance) that would naturally dictate the direction of treatment. We also present a series of consecutive stepped treatment algorithms based on evidence-based practice and modelled on naturalistic care that we believe could be adapted to multicentre settings as a template for the translational researcher to aid in the design of pragmatic treatment trials that are capable of identifying biomarkers of treatment response or non-response at each key stage of the evidence-based canon.

Physical ill-health is a common feature of depression. Cardiovascular disease, type 2 diabetes and cancer are, for example, common occurrences and lead to increased morbidity and mortality. The question arises whether these changes are attributable to an unhealthy life style or due to genetic or other causes that are exacerbated by stress and adverse environmental factors. Of the various factors which have been implicated, chronic low-grade inflammation has received much attention in recent years. For this reason, the following review assesses the evidence that implicates inflammation in the psychopathology of major depression and how this is linked to the increased incidence of physical illness in these patients.