Chapter 2: Clinical Need and Rationale for Multi-Target Drugs in Psychiatry

High attrition in attempts to discover new pharmacological agents for the treatment of psychiatric disorders has triggered a decline in R&D investment in important disease categories such as schizophrenia and mood disorders. Poor knowledge about disease molecular pathology and molecular target validation coupled with notable costly failures involving clinical trials with highly novel and selective single target agents (STAs) have contributed to the development of this trend. One positive development arising from the current situation is the renewed interest in investigating approaches involving multi-target agents (MTAs), which have historically shown a strong track record of success and utility in the treatment of psychiatric disorders. However, it is clear that the traditional serendipity-dependent drug discovery approach for multi-target agents is suboptimal and has to evolve towards a new model of rationally designed and tailored MTAs. It is of course highly challenging to optimise compounds across several therapeutic targets whilst minimising potential broad receptor promiscuity as well as other properties to generate high quality drug candidates. Nevertheless, recent developments in medicinal chemistry approaches and pharmacological evaluation suggest that feasibility for tailored MTAs is not unrealistic. Appropriately designed MTAs, such as hybrids of validated and unprecedented novel molecular targets, offer a multi-functional pharmacology with the potential for multi-symptomatic efficacy and multi-indicational use. If successful this will help to address the compelling unmet medical need and the treatment requirements of schizophrenia and mood disorder patients as well as easing the burden of carers and the societal costs arising from these devastating illnesses.