Developing More Efficacious Antidepressant Medications: Improving and Aligning Preclinical and Clinical Assessment Tools

Depression is, according to the World Health Organization, among the top five causes of disability and is a major healthcare problem and thus a serious economic burden for society. Current treatments for depression and anxiety disorders are of limited efficacy in many patients and are associated with side effects that reduce compliance in others. As all antidepressants currently used exert their primary pharmacological action by altering serotonergic and/or noradrenergic pathways in the brain, substantial research efforts have been directed toward the potential to develop novel, more effective, non-monoamine-based antidepressant medications. To date, this has proved very difficult and along the way there have been a number of high-profile casualties, most notably the Neurokinin (NK)-1 receptor antagonists, which demonstrated an excellent preclinical portfolio but failed in clinical trials. All of the present preclinical tests available in depression research were developed after the clinical introduction of the first generation of antidepressants, the Tricyclic Antidepressants (TCAs), and monoamine oxidase inhibitors and are more appropriately viewed as tests predictive of antidepressant-activity, or even more reductionistically, as tests of enhanced monoamine function. There is a shift away from these traditional animal models to more focused research dealing with an endophenotype-style approach, selective breeding programs and incorporation of new findings from human neuroimaging and genetic studies. Moreover, advances in neuroimaging and in biomarker development also inform the clinical testing of novel drugs. This chapter assesses these new directions and the potential impact that they could have in developing novel therapeutics for depression where there is a huge unmet medical need.