Final Report Summary - NEWMOOD (New molecules in mood disorders: a genomic, neurobiological and systems approach in animal models and human disorder)
Depression is common and affects twice as many women as men. In the global burden of disease survey, it is the fourth most prevalent cause of disability, greater than e.g. cardiovascular disease. Gender, social and familial factors increase risk for depression, but little is known about how these influences work in the brain, least of all at the molecular level. Newer antidepressant treatments still act in the same way as 30 years ago and their downstream molecular actions are obscure. At most 65 % of new episodes respond to drug-treatment and chronic, treatment-resistant depression is a major health burden.
The major objective of NEWMOOD is in its acronym - to identify new molecules for mood disorders. At the heart of the NEWMOOD strategy were gene-expression studies which aimed to identify genes whose expression is changed (how much they are turned on or off) in a number of animal models of vulnerability to depression. The candidate genes were then confirmed in humans principally by demonstrating that allelic variation (the activity of the two genes inherited one from each parent) in candidate genes is associated with variation in biomarkers for vulnerability such as emotionality and a bias to detecting negative information. Further validation was sought by determining whether the genes overexpressed in the brain in animal models are also overexpressed in human post-mortem brain from patients with depression.
In humans, vulnerability to depression appears to act by sensitising individuals to the triggering effect of adverse life events especially in the setting of current chronic social adversity. One endophenotypic marker for vulnerability is the personality trait of neuroticism which has a heritability of about 0.5 and is known from prospective studies to greatly amplify the risk of depression following a life event, especially in the setting of chronic social adversity. Adversity early in life such as neglect, parental loss or abuse, is also a vulnerability factor that acts to increase the potency of life events. NEWMOOD has attempted to model genetic vulnerability using Genetically modified (GM) mice. Maternal separation (MS) and Chronic mild stress (CMS) model early and late psychosocial stress. Giving up struggling in an inescapable situation and reduced preference for sucrose model respectively the hopelessness and anhedonia of the depressed state. Combining these translational measures with the NEWMOOD expression array data and with human SNP associations offers a unique opportunity to rapidly validate the new candidate genes identified through the array studies.
NEWMOOD has established a comprehensive translational dataset in rodents and humans that has yielded a multilevel integrated account of the pathogenesis of depression. The Illumina array gene expression data has taken the account to its deepest molecular level, the ultimate task of NEWMOOD, securely tied to a superstructure of carefully validated behaviours through intervening brain processes. Where possible at each level the processes have been translated to and from humans and rodents. The superstructure is important in validating the molecular translation: we can say not only that the same genes affect vulnerability in rodents and humans but also that they do so through similar processes. We have reached this state for several genes - the CB1 cannabis receptor, the 5-HT transporter, Tryptophan hydroxylase 2, 5-HT1A and 5HT1B receptors and brain-derived neurotrophic factor (BDNF). The project ultimately believes they can offer a new hypothesis-testing way to proceed in detecting molecular mechanisms in depression.
The knowledge gained through NEWMOOD will lead to a better understanding of the molecular mechanisms in the causation of depression, and ultimately should help the development of new and effective drug-treatments. However, although some 'potential commercial applications, products, processes or services' could be eventual goals, these will not occur during the lifetime of the project or fall within the exploitation activities directly linked to the project.
The major objective of NEWMOOD is in its acronym - to identify new molecules for mood disorders. At the heart of the NEWMOOD strategy were gene-expression studies which aimed to identify genes whose expression is changed (how much they are turned on or off) in a number of animal models of vulnerability to depression. The candidate genes were then confirmed in humans principally by demonstrating that allelic variation (the activity of the two genes inherited one from each parent) in candidate genes is associated with variation in biomarkers for vulnerability such as emotionality and a bias to detecting negative information. Further validation was sought by determining whether the genes overexpressed in the brain in animal models are also overexpressed in human post-mortem brain from patients with depression.
In humans, vulnerability to depression appears to act by sensitising individuals to the triggering effect of adverse life events especially in the setting of current chronic social adversity. One endophenotypic marker for vulnerability is the personality trait of neuroticism which has a heritability of about 0.5 and is known from prospective studies to greatly amplify the risk of depression following a life event, especially in the setting of chronic social adversity. Adversity early in life such as neglect, parental loss or abuse, is also a vulnerability factor that acts to increase the potency of life events. NEWMOOD has attempted to model genetic vulnerability using Genetically modified (GM) mice. Maternal separation (MS) and Chronic mild stress (CMS) model early and late psychosocial stress. Giving up struggling in an inescapable situation and reduced preference for sucrose model respectively the hopelessness and anhedonia of the depressed state. Combining these translational measures with the NEWMOOD expression array data and with human SNP associations offers a unique opportunity to rapidly validate the new candidate genes identified through the array studies.
NEWMOOD has established a comprehensive translational dataset in rodents and humans that has yielded a multilevel integrated account of the pathogenesis of depression. The Illumina array gene expression data has taken the account to its deepest molecular level, the ultimate task of NEWMOOD, securely tied to a superstructure of carefully validated behaviours through intervening brain processes. Where possible at each level the processes have been translated to and from humans and rodents. The superstructure is important in validating the molecular translation: we can say not only that the same genes affect vulnerability in rodents and humans but also that they do so through similar processes. We have reached this state for several genes - the CB1 cannabis receptor, the 5-HT transporter, Tryptophan hydroxylase 2, 5-HT1A and 5HT1B receptors and brain-derived neurotrophic factor (BDNF). The project ultimately believes they can offer a new hypothesis-testing way to proceed in detecting molecular mechanisms in depression.
The knowledge gained through NEWMOOD will lead to a better understanding of the molecular mechanisms in the causation of depression, and ultimately should help the development of new and effective drug-treatments. However, although some 'potential commercial applications, products, processes or services' could be eventual goals, these will not occur during the lifetime of the project or fall within the exploitation activities directly linked to the project.
