The past 5 years have seen unprecedented changes in the approach to developing new therapeutic drug treatments. Perhaps the most significant changes have taken place in the area of clinical development with a move away from determining efficacy exclusively in traditional phase II clinical trials in patients, to earlier development phases in which efficacy is inferred from experimental studies with healthy volunteers and/or surrogate patient groups. It is not difficult to identify the drivers for such change. In the last decade the cost of drug development has been subject to double-digit year-onyear inflation while the rate of productivity of new drugs remains stubbornly low at approximately 10 per year and falling (Munos, 2009). Moreover, with the development and opportunity costs of each new drug now in excess of 1 billion (DiMasi et al. 2003; Munos, 2009) and the revenues from highly profitable drugs dwindling due to patent expiry, it is little wonder that the outlook for the pharmaceutical industry is increasingly uncertain and the mood is sombre. Nowhere has this been more profoundly experienced than in psychiatry where two large Pharma companies, GlaxoSmithKline and AstraZeneca, recently announced the closure of their discovery research divisions (Miller, 2010). From a commercial business perspective the reasons for these withdrawals are very clear: the prospect of a significant return on capital invested in the discovery of drugs for psychiatric disorders is too low compared with other therapeutic areas to warrant further investment. Thus, despite significant advances in our understanding of brain chemistry, circuitry and function in the last 20 years, these developments have not been sufficient to enable rational development of drug therapies for psychiatric disorders. Part of the problem stems from the empirical observation that promising effects of novel compounds in animals do not reliably predict efficacious effects in patients (Pangalos et al., 2007). This lack of translation from animal models to clinical efficacy makes it difficult to generate human models of psychiatric disease that provide a stepping stone to the large, expensive phase III patient trials required for drug registration. Ironically, however, just as large Pharma companies are reconsidering their commitment to discovering and developing new treatments for psychiatric disorders new approaches to developing and validating human experimental medicine models of the disorders are finally emerging. In this special issue leading researchers review new advances in experimental medicine models and approaches in the areas of anxiety, depression, schizophrenia, cognitive disorders, drug addiction and sleep disorders. They also provide an evaluation of the latest advances in functional magnetic resonance imaging (fMRI), pharmacofMRI (pfMRI) and electroencephalography (EEG) as well emerging technologies such as magnetoencephalography (MEG). These articles articulate some of the latest theories, techniques and technologies that are now being brought to bear in this challenging area. They also highlight recent advances in areas where real progress has been made and the directions that hold significant promise for future drug development in psychiatry. Progress in the development of experimental medicine approaches is particularly apparent in the area of depression. Approximately 14% of the Western European population have a lifetime history of any mood disorder (Alonso et al., 2004). The extent of this problem is also reflected in the large worldwide sales of antidepressants (more than US$19.4 billion in 2007) (CNS Drug Discoveries: Depression, 2008). They are often less than perfect drugs with a significant side effect burden such as sleep disturbance or sexual dysfunction (Hansen et al., 2005). However, perhaps the greatest problem is that a significant proportion of patients are ‘treatment resistant’: their depression is not significantly relieved by two or more courses of treatment with different antidepressants (Howland et al., 2011). Consequently the need for new treatments is undeniable, but in this area the standard animal models of tail suspension, forced swimming and mild chronic stress lack the precision and sophistication required to model such a complex disorder as depression. The traditional theory of antidepressant drug action postulates that treatment with an antidepressant, e.g. a selective serotonin reuptake inhibitor (SSRI), results in downstream neuroadaptive changes which take some time to occur but eventually lead to an elevation in mood. More recently, Harmer et al. (2011a) have proposed that antidepressants
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Jan 1, 2024
David De Bandt + 4
Open Access
