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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 1 Current depression landscape: a state of the field today
More than two dozen pharmacological treatments are currently available for depression, working by more than a half dozen mechanisms, yet there remain many unmet therapeutic needs. Available antidepressants act directly on monoamine mechanisms, influencing receptors and transporters for serotonin, norepinephrine, and/or dopamine. Truly novel therapeutic targets beyond the monoamines have not emerged in the past few decades. Advances have been mostly in improved tolerability, and as a result, limitations in efficacy persist for all agents in the antidepressant class. Specifically, far too few patients, perhaps only a third, attain a full remission of symptoms, and those who have had many episodes of depression are not likely to sustain any remission for more than a few months. Thus, there is the urgent need for antidepressants with improved efficacy. Although the “holy grail” of antidepressant treatment has long been rapid onset of action, the reality is that more robust and sustained efficacy, even if delayed, is the unmet need of today. This is unlikely to be met by targeting the same monoamine transporters and receptors where current antidepressants act, so novel therapeutic targets must be identified if there is to be novel therapeutic efficacy of more robust and sustained antidepressant action.
Other issues in the treatment of depression include the increasing confusion between unipolar and bipolar depression, particularly at onset of first depressive episodes, as well as the confusion between treatment-resistant unipolar depression versus difficult-to-treat rapid cycling, mixed episodes of bipolar depression. Treatments for bipolar depression such as anticonvulsants and atypical antipsychotics are increasingly being used for bipolar and treatment-resistant cases. Future therapeutics may usefully exploit these mechanisms, and treatment of difficult cases in the future will likely involve use of multiple simultaneous mechanisms, either with multiple drugs or with multifunctional drugs.
There is also concern that depression may be a progressive illness, with unipolar depression progressing to treatment-resistant depression or even to bipolar spectrum disorder, and bipolar disorder progressing to rapid cycling and mixed treatment-resistant bipolar episodes. Future treatments of depression may not only have the potential to treat current symptoms and prevent their relapse, but also to halt progression and thus be disease-modifying, altering the course of untreated or inadequately treated illness.