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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 2 Novel therapeutic targets for treating affective disorders
Prevalence of depression has increased progressively over the last decades. Besides the impact on human quality of life, the pharmaco-economical impact of this syndrome requires ongoing development of newer, more powerful antidepressants. While optimizing existing therapeutic compounds, multiple approaches can be taken to generate superiority over these compounds. The delay in onset of action of antidepressants is of relevance as the presence of side effects during the initial absence of clinical effects causes low therapy compliance. Obviously, a decrease in onset of action would overcome this problem. Current therapy still induces considerable side effects depending on the class of antidepressants used. Reducing these has multiple advantages, such as it will increase compliance but also facilitate the rapid and safe initiation of drug treatment. In line with safety requirements is the notion that new antidepressants should not be prone to hazardous effects in overdose, nor should they induce dangerous interactions by interfering with other treatment. Finally, it is currently recognized that depression is a cluster of symptoms rather than a concise disease. To this end, it is recognized that more tailored treatments might be required in the future. Arguably targeting subsymptoms and comorbid features such as anxiety are of high relevance. Attempts to improve antidepressants have been made into monoamine-related strategies, but also more recently in non-monoamine strategies. The effectiveness of monoamine-targeted selective, dual- and triple-uptake inhibitors and augmented uptake inhibitors is discussed. In addition, new strategies such as monoamine non-uptake inhibitor drugs or non-monoamine drugs exerting effects on Glu, gamma-aminobutyric acid (GABA), Substance P, and acetylcholine are discussed, as are more miscellaneous approaches.