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Reviews the future of mood-disorder research, covering identification of new therapeutic targets, preclinical models, and medicinal chemistry opportunities, and increasing understanding of genetic influences. Essential reading for everyone involved in psychopharmacology development, and mental health clinicians seeking a preview of discoveries soon to influence their practice.
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As the World Health Organization estimates that depression will become the second leading cause of death by the year 2020 – due primarily to complications arising from stress and the cardiovascular system – the need to develop novel and more effective treatment strategies for patients suffering with mood disorders has never been more paramount. Current treatment options for depressed patients include a variety of molecules designed to exclusively elevate central nervous system levels of monoamines such as serotonin (5-HT). These classes include the monoamine oxidase inhibitors and tricyclics and are exemplified by the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin/norepinephrine reuptake inhibitors (SNRIs). While these medicines are moderately effective in some patient populations, there are still considerable limitations associated with all commercially available antidepressants. These drawbacks include, but are not limited to, delayed onset of efficacy, treatment resistance in many patients, and deleterious side effects such as emesis and sexual dysfunction. The focus of this book is to review the current landscape and state of the field for depression research with an eye towards shedding light on where the future of mood disorders research is headed in terms of novel therapeutic targets, preclinical model development, exploring depression endophenotypes, and medicinal chemistry strategies. Undoubtedly all of these disciplines, as well as others including genetics and translational medicine approaches, will need to successfully collaborate to help build a better understanding of disease etiology, patient stratification, and treatment. As depression research has evolved over the past 50 years, the next decade will be instrumental in facilitating a move beyond our current understanding and pharmacological treatment options, and strive to discover and develop more personalized and effective treatment options for the millions of patients suffering from chronic and debilitating mood disorders.
Chad E. Beyer, PhD, MBAChapter 1 |
Chapter 5 |
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Current depression landscape: a state of the field today | Defining depression endophenotypes |
Chapter 2 |
Chapter 6 |
Novel therapeutic targets for treating affective disorders | Genetic and genomic studies of major depressive disorder |
Chapter 3 |
Chapter 7 |
Developing novel animal models of depression | Medicinal chemistry challenges in the design of next generation antidepressants |
Chapter 4 |
Chapter 8 |
Translational research in mood disorders: using imaging technologies in biomarker research | Application of pharmacogenomics and personalized medicine for the care of depression |
Chapter 5 Defining depression endophenotypes
It is widely assumed that major depressive disorder (MDD) includes a heterogeneous mix of conditions reached through multiple etiological and pathophysiological processes. In recent years, efforts to parse the heterogeneity inherent to MDD have led to renewed interest in identifying potential depressive “endophenotypes” – intermediate phenotypes hypothesized to lie within the etiological link between genes and clinical disease. In this chapter, we begin with an overview of the endophenotype concept and its central criteria (clinical and biological plausibility, specificity, state-independence, heritability, familial association, and cosegregation). Next, we examine the potential utility of applying an endophenotypic approach to depression research, with a focus on anhedonia as a particularly promising depressive endophenotype. To this end, we review and integrate findings across epidemiological, behavioral, neuroimaging, and genetic studies to assess anhedonia within the endophenotypic criteria. Following this examination, we discuss current directions in the development of objective laboratory-based measures of anhedonia and their value in facilitating a more precise identification of the psychological and neurobiological mechanisms underlying anhedonia. We conclude that utilizing an endophenotypic approach may improve our understanding of the etiology and pathophysiology of depression, which would ultimately enhance our ability to design more effective treatment and prevention strategies.