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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 3 Developing novel animal models of depression
Although the mechanism of action of current antidepressant drugs is well known, 30% of patients remain refractory to treatment. There are examples of recent failures of antidepressant clinical development programs that reinitiate the discussion on the reliability, or predictability of animal models of major depressive disorder. The comorbid expression of depression is well known in many neurological and psychiatric diseases, including drug abuse. Symptoms such as anhedonia, hypo- or hyperlocomotor activity, sleep disturbances, and weight loss can be measured in animals, but the overreliance on such readouts may lead to misinterpretations of their relevance to the clinical situation. Existing models are mainly based, or could be considered to have an overreliance, on the putative involvement of monoaminergic systems. Data recorded from these existing models do result in clinical candidate nomination, but when such compounds reach the clinic, data often do not fully meet expectations. From a preclinical point of view, the integration of the range of established and novel technologies, such as monitoring dynamic changes in extracellular neurotransmitters, behavioral readouts, electrophysiological recordings, and brain scanning (e.g. using functional magnetic resonance imaging and spectroscopy, PET, SPECT imaging) is critically needed in the development of new animal models, as is the translation of such approaches to the clinic and vice versa. This integration is needed across the gamut of indication areas of key interest.