From monoamines to genomic targets: a paradigm shift for drug discovery in depression View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2004-02-01

AUTHORS

Ma-Li Wong, Julio Licinio

ABSTRACT

Key PointsDepression is one of the world's most lucrative drug targets.This common and complex disorder of gene–environment interactions affects more than 10% of the world's population.In spite of the public health relevance and economic importance of depression, existing drug targets are based on the old monoamine theory.All available drugs bind to targets identified more than 30 years ago. The enormous progress in neuroscience, molecular biology and genomics that has occurred in the past three decades has not been translated into novel treatment strategies.We have created a conceptual framework that summarizes the progress in antidepressant drug development in terms of three 'waves'.The first wave of antidepressant development took place in the early post-World War II period, in a time of therapeutic revolution that constituted the birth of modern pharmacology. The first antidepressant described was initially tested for its ability to treat tuberculosis, but was found to have the remarkable side effect of increasing patients' levels of energy. Research determined that the serendipitiously discovered tricyclic antidepressants target monominergic systems.The second wave of antidepressant development consisted of the development of newer drugs acting on monoaminergic systems with increasing tolerability and safety. Selective reuptake inhibitors (SRIs) have been developed to enhance the function of specific monoamine systems by increasing the availability of a monoamine as a result of blockade of presynaptic transporters, which promote reuptake, thereby increasing transmitter availability at the synaptic cleft. SRIs have the same efficacy but are better tolerated than tricyclics.The third wave of antidepressant development represents a paradigm shift, consisting in turn of three parallel strategies.The first of those strategies is based on drug development based on candidate systems elucidated by contemporary translational neuroscience. Those systems include neuropeptides, such as corticotripin-releasing hormone (CRH) and substance P. Emerging targets are based on the neuroimmune, neuroprotection, and neurogenesis hypotheses of depression. The role of the transcription factor, cAMP response element-binding protein (CREB), as a potential target in depression has been increasingly investigated.The second strategy consists of pharmacogenomic approaches to the identification of new targets for drug development and for prediction of treatment response.The last strategy is still in its conceptual phase and will be based on aetiological models and opportunities emerging from genetics. Depression susceptibility genes might be targets for drug development or could identify previously unrecognized pathways for novel therapies. More... »

PAGES

136-151

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  • Journal

    TITLE

    Nature Reviews Drug Discovery

    ISSUE

    2

    VOLUME

    3

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nrd1303

    DOI

    http://dx.doi.org/10.1038/nrd1303

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1003179281

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/15040578


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        "description": "Key PointsDepression is one of the world's most lucrative drug targets.This common and complex disorder of gene\u2013environment interactions affects more than 10% of the world's population.In spite of the public health relevance and economic importance of depression, existing drug targets are based on the old monoamine theory.All available drugs bind to targets identified more than 30 years ago. The enormous progress in neuroscience, molecular biology and genomics that has occurred in the past three decades has not been translated into novel treatment strategies.We have created a conceptual framework that summarizes the progress in antidepressant drug development in terms of three 'waves'.The first wave of antidepressant development took place in the early post-World War II period, in a time of therapeutic revolution that constituted the birth of modern pharmacology. The first antidepressant described was initially tested for its ability to treat tuberculosis, but was found to have the remarkable side effect of increasing patients' levels of energy. Research determined that the serendipitiously discovered tricyclic antidepressants target monominergic systems.The second wave of antidepressant development consisted of the development of newer drugs acting on monoaminergic systems with increasing tolerability and safety. Selective reuptake inhibitors (SRIs) have been developed to enhance the function of specific monoamine systems by increasing the availability of a monoamine as a result of blockade of presynaptic transporters, which promote reuptake, thereby increasing transmitter availability at the synaptic cleft. SRIs have the same efficacy but are better tolerated than tricyclics.The third wave of antidepressant development represents a paradigm shift, consisting in turn of three parallel strategies.The first of those strategies is based on drug development based on candidate systems elucidated by contemporary translational neuroscience. Those systems include neuropeptides, such as corticotripin-releasing hormone (CRH) and substance P. Emerging targets are based on the neuroimmune, neuroprotection, and neurogenesis hypotheses of depression. The role of the transcription factor, cAMP response element-binding protein (CREB), as a potential target in depression has been increasingly investigated.The second strategy consists of pharmacogenomic approaches to the identification of new targets for drug development and for prediction of treatment response.The last strategy is still in its conceptual phase and will be based on aetiological models and opportunities emerging from genetics. Depression susceptibility genes might be targets for drug development or could identify previously unrecognized pathways for novel therapies.", 
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