Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology

Abstract

Background: There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology.

Methods: Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery.

Results: We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities.

Conclusions: We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

Keywords: New medications; Psychiatric disorder; Psychiatric drug discovery; Systems neurosciencese.

Fig. 1

Schematic diagram to illustrate how in theory the 8 principles (identified by digits) might enhance CNS drug discovery (when applied in the sequence indicated by arrows, from left to right). Basic neuroscience feeds into the definition of disease phenotypes that define targets, and the generation of disease-relevant perturbations. Test molecules are generated from a variety of platforms including medicinal chemistry. Molecules are tested in animal and humans using translational methods and paradigms. Targets are validated and clinical efficacy tested via collaborative studies. Results of studies are fed back to validate, or otherwise, the methods employed, or the molecule tested, or its clinical target

Fig. 2

Schematic diagram to illustrate how in practice the 8 principles (identified by digits), applied in the sequence identified by arrows, might enhance CNS drug discovery, in the case of a specific example, drugs to enhance cognition in schizophrenia. See legend to Fig. 1 for further description. Not all medications would necessarily require deployment of all 8 principles