1,721,173 research outputs found
2016 Golden Helix Summer School - Cancer Genomics and Individualized Therapy. 22-26 September 2016, Syros Island, Greece: Abstracts
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Treatment-Resistant Schizophrenia : Insights From Genetic Studies and Machine Learning Approaches
Full text linkSchizophrenia (SCZ) is a severe psychiatric disorder affecting approximately 23 million people worldwide. It is considered the eighth leading cause of disability according to the Wood Health Organization and is associated with a significant reduction in life expectancy. Antipsychotics represent the first-choice treatment in SCZ, but approximately 30% of patients fail to respond to acute treatment. These patients are generally defined as treatment-resistant and are eligible for clozapine treatment. Treatment-resistant patients show a more severe course of the disease, but it has been suggested that treatment-resistant schizophrenia (TRS) may constitute a distinct phenotype that is more than just a more severe form of SCZ. TRS is heritable, and genetics has been shown to play an important role in modulating response to antipsychotics. Important efforts have been put into place in order to better understand the genetic architecture of TRS, with the main goal of identifying reliable predictive markers that might improve the management and quality of life of TRS patients. However, the number of candidate gene and genome-wide association studies specifically focused on TRS is limited, and to date, findings do not allow the disentanglement of its polygenic nature. More recent studies implemented polygenic risk score, gene-based and machine learning methods to explore the genetics of TRS, reporting promising findings. In this review, we present an overview on the genetics of TRS, particularly focusing our discussion on studies implementing polygenic approaches
Personalized medicine in bipolar disorder: how can we overcome the barriers to clinical translation?
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We are not alone in our body: insights into the involvement of microbiota in the etiopathogenesis and pharmacology of mental illness
No full textBackground: The etiopathogenesis of psychiatric disorders is still not completely understood. Growing evidence supports the hypothesis that mental illness and related disturbances do not necessarily originate in the brain. Inflammation has been suggested to play a central role in psychiatric disorders and altered levels of peripheral cytokines have been reported in several studies. Recently, it has emerged that bacteria populating the human gut could modulate low-grade inflammation, as well as high-order brain functions, including mood and behavior. These bacteria constitute the microbiota, a large population comprising 40,000 bacterial species and 1,800 phila involved in key processes important to maintain body homeostasis. Method: In this review, we present and discuss studies exploring the role of dysbiosis and products of the gutmicrobiota in the pathogenesis of psychiatric disorders, as well as their potential involvement in mediating the effect of antidepressants, mood stabilizers, and antipsychotics. Results: Although this field is still at its early stage of development, a growing number of studies suggest that an altered composition of the gut microbiota, together with translocation of bacterial products into the systemic circulation, might play a role in the pathogenesis of psychiatric disorders as well as in response to psychotropic medications. Conclusion: An altered composition and functioning of gut microbiota have been reported in psychiatric disorders, and recent findings suggest that gut bacteria could be involved in modulating the efficacy of psychotropic medications
Lithium pharmacogenetics: Where do we stand?
No full textPreclinical Research Bipolar disorder (BPD) is a chronic and disabling psychiatric disorder with a prevalence of 0.8-1.2% in the general population. Although lithium is considered the first-line treatment, a large percentage of patients do not respond sufficiently. Moreover, lithium can induce severe side effects and has poor tolerance and a narrow therapeutic index. The genetics of lithium response has been largely investigated, but findings have so far failed to identify reliable biomarkers to predict clinical response. This has been largely determined by the highly complex phenotipic and genetic architecture of lithium response. To this regard, collaborative initiatives hold the promise to provide robust and standardized methods to disantenagle this complexity, as well as the capacity to collect large samples of patietnts, a crucial requirement to study the genetics of complex phenotypes. The International Consortium on Lithium Genetics (ConLiGen) has recently published the largest study so far on lithium response reporting significant associations for two long noncoding RNAs (lncRNAs). This result provides relevant insights into the pharmacogenetics of lithium supporting the involvement of the noncoding portion of the genome in modulating clinical response. Although a vast body of research is engaged in dissecting the genetic bases of response to lithium, the several drawbacks of lithium therapy have also stimulated multiple efforts to identify new safer treatments. A drug repurposing approach identified ebselen as a potential lithium mimetic, as it shares with lithium the ability to inhibit inositol monophosphatase. Ebselen, an antioxidant glutathione peroxidase mimetic, represents a valid and promising example of new potential therapeutic interventions for BD, but the paucity of data warrant further investigation to elucidate its potential efficacy and safety in the management of BPD. Nevertheless, findings provided by the growing field of pharmacogenomic research will ultimately lead to the identification of new molecular targets and safer treatments for BP
The Role of Pharmacogenomics in Bipolar Disorder: Moving Towards Precision Medicine
No full textBipolar disorder (BD) is a common and disabling psychiatric condition with a severe socioeconomic impact. BD is treated with mood stabilizers, among which lithium represents the first-line treatment. Lithium alone or in combination is effective in 60% of chronically treated patients, but response remains heterogenous and a large number of patients require a change in therapy after several weeks or months. Many studies have so far tried to identify molecular and genetic markers that could help us to predict response to mood stabilizers or the risk for adverse drug reactions. Pharmacogenetic studies in BD have been for the most part focused on lithium, but the complexity and variability of the response phenotype, together with the unclear mechanism of action of lithium, limited the power of these studies to identify robust biomarkers. Recent pharmacogenomic studies on lithium response have provided promising findings, suggesting that the integration of genome-wide investigations with deep phenotyping, in silico analyses and machine learning could lead us closer to personalized treatments for BD. Nevertheless, to date none of the genes suggested by pharmacogenetic studies on mood stabilizers have been included in any of the genetic tests approved by the Food and Drug Administration (FDA) for drug efficacy. On the other hand, genetic information has been included in drug labels to test for the safety of carbamazepine and valproate. In this review, we will outline available studies investigating the pharmacogenetics and pharmacogenomics of lithium and other mood stabilizers, with a specific focus on the limitations of these studies and potential strategies to overcome them. We will also discuss FDA-approved pharmacogenetic tests for treatments commonly used in the management of BD
Mood Disorders, Accelerated Aging, and Inflammation : Is the Link Hidden in Telomeres?
Full text linkMood disorders are associated with an increased risk of aging-related diseases, which greatly contribute to the excess morbidity and mortality observed in affected individuals. Clinical and molecular findings also suggest that mood disorders might be characterized by a permanent state of low-grade inflammation. At the cellular level, aging translates into telomeres shortening. Intriguingly, inflammation and telomere shortening show a bidirectional association: a pro-inflammatory state seems to contribute to aging and telomere dysfunction, and telomere attrition is able to induce low-grade inflammation. Several independent studies have reported shorter telomere length and increased levels of circulating inflammatory cytokines in mood disorders, suggesting a complex interplay between altered inflammatory-immune responses and telomere dynamics in the etiopathogenesis of these disorders. In this review, we critically discuss studies investigating the role of telomere attrition and inflammation in the pathogenesis and course of mood disorders, and in pharmacological treatments with psychotropic medications
Method for the assessment of pharmacogenetic response to treatment with lithium salts in bipolar disorder
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