Pathways to new drug discovery in neuropsychiatry

BMC Medicine, Nov 2012

There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success. See related article http://www.biomedcentral.com/1741-7015/10/150

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Pathways to new drug discovery in neuropsychiatry

Mi h l B rk 0 0 Deakin University, School of Medicine , Barwon Health, P.O. Box 291, Geelong, 3220 , Australia There is currently a crisis in drug discovery for neuropsychiatric disorders, with a profound, yet unexpected drought in new drug development across the spectrum. In this commentary, the sources of this dilemma and potential avenues to redress the issue are explored. These include a critical review of diagnostic issues and of selection of participants for clinical trials, and the mechanisms for identifying new drugs and new drug targets. Historically, the vast majority of agents have been discovered serendipitously or have been modifications of existing agents. Serendipitous discoveries, based on astute clinical observation or data mining, remain a valid option, as is illustrated by the suggestion in the paper by Wahlqvist and colleagues that treatment with sulfonylurea and metformin reduces the risk of affective disorder. However, the identification of agents targeting disorder-related biomarkers is currently proving particularly fruitful. There is considerable hope for genetics as a purist, pathophysiologically valid pathway to drug discovery; however, it is unclear whether the science is ready to meet this promise. Fruitful paradigms will require a break from the orthodoxy, and creativity and risk may well be the fingerprints of success. See related article http://www.biomedcentral.com/ 1741-7015/10/150 2012 Berk; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. - Introduction Before applying a microscope to a problem, it is always wise to first use a wide-angle lens. In psychiatric disorders, as in most of medicine, the two things that matter most to people with disorders are the availability of effective treatments for those disorders and the capacity to prevent these disorders occurring in the first instance. With regard to the latter, psychiatry is only beginning to develop an evidence base of potentially plastic risk factors for the development of common mental disorders. Existing treatments for most major psychiatric disorders are limited in terms of their efficacy and tolerability. The situation in terms of new drug development is best summarized by Steven Hyman, a previous director of the US National Institute of Mental Health (NIMH) director, who stated that, Drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression, and common forms of autism. Despite high prevalence and unmet medical need, major pharmaceutical companies are deemphasizing or exiting psychiatry, thus removing significant capacity from efforts to discover new medicines [1]. Pathways to drug discovery How did we get into this pickle? And how can we extricate ourselves? To answer this, it is necessary we look at the pathways to drug discovery and critically analyze which of these are fruitful paths to drug discovery and what new avenues might be open. The initial path has been that of serendipity. Almost all psychotropic agents have been discovered accidentally, their mechanisms of action reverseengineered, and new agents developed that, in some cases, have improved on the originals. Lithium, the antipsychotics, and the antidepressants all fall into this class. Indeed, most of our knowledge of the neurobiology of neuropsychiatric disorders derives from this process; this includes the dopamine theory of schizophrenia and the monoamine theory of antidepressants [2]. Sadly, the rewards deriving from this path seem to be dwindling. At least part of the problem arises from the fact that these agents have been utilized for proof of concept in animal models of these disorders, and these models in a circular manner seem to reflect the profile of the original agents and are of dubious value in detecting novel mechanisms [3]. Nevertheless, both astute clinical examination, and observational studies of unexpected benefits of agents used for other indications, remain valuable avenues for drug discovery, despite their lack of a primary, pathophysiologically grounded scientific process. In this context, the paper by Wahlqvist et al. [4], which used a retrospective case-control study of data from the Taiwanese National Health Insurance database to examine whether people taking a sulfonylurea and/or metformin had a lower incidence of depression, is noteworthy. The authors reported that patients with diabetes taking sulfonylurea or metformin had a lower incidence of depression than people not taking these anti-diabetic agents [4]. This is not entirely unexpected. There are published data suggesting that pioglitazone, an oral anti-diabetic agent, also has antidepressant properties [5]. The hypothesis leading the authors (...truncated)


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Michael Berk. Pathways to new drug discovery in neuropsychiatry, BMC Medicine, 2012, pp. 151, 10, DOI: 10.1186/1741-7015-10-151