Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

Abstract

Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than 'conventional treatment' Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds.

The Presynaptic Component of the Serotonergic System is Required for Clozapine's Efficacy

“…Because many serotonin receptors are both pre-and post-synaptic with respect to serotonin neurons, it was not clear whether the requirement for serotonergic engagement would be pre-or postsynaptic, although current hypotheses posit a selective effect of clozapine on postsynaptic serotonin receptors (eg, HTR2A, HTR2C, HTR6, and HTR7; Conn and Roth, 2008;Roth et al, 2004). These hypotheses predict that deletion of the presynaptic component of the serotonin neuronal system would not affect clozapine's therapeutic actions.…”

“…This hypothesis has led to a new crop of muscarinic subtype-selective allosteric potentiators currently being developed (Conn and Roth, 2008;Gray and Roth, 2007). Furthermore, it has also been shown that clozapine can potentiate NMDA activity by directly binding to glycine B site (Bressan et al, 2005;Javitt et al, 2005;Schwieler et al, 2008), thus contributing to its unique clinical efficacy.…”

“…The targets interrogated included both validated antipsychotic drug targets (eg, D2, D3 dopamine; 5-HT 2A serotonin) as well as most of the currently investigated targets (eg, M1, M4 muscarinic; mGluR2/3 metabotropic glutamate; nicotinic acetylcholine) (Conn and Roth, 2008;Gray and Roth, 2007;Jensen et al, 2008). We then performed hierarchical clustering analysis to identify atypical antipsychotic drugs that were most similar to clozapine and typical antipsychotic drugs that were most dissimilar.…”

“…It is currently unknown, and the subject of considerable controversy, which, if any, of these pharmacological properties are essential for either the unique spectrum of efficacy or the unusual sideeffect profile of clozapine. One aspect of their actions that has recently become clear, however, is the observation that only clozapine and the closely related atypical antipsychotic drugs are effective in genetic and pharmacological models that mimic the NMDA-receptor hypofunction of schizophrenia Bakshi et al, 1994;Belforte et al, 2010;Mohn et al, 1999) Without a clearer understanding of the molecular and neuronal substrates responsible for these actions, it will remain difficult, if not impossible, to develop new antipsychotic drugs with either improved efficacies or fewer side effects (Conn and Roth, 2008).…”

Grand Challenges for Psychiatric Drug Discovery: A Perspective

“…The three papers authored by Conn and Roth (Conn and Roth, 2008;see p. 2048), Carpenter and Koenig (Carpenter and Koenig, 2007;see p. 2061), and Mathew et al (Mathew et al, 2008;see p. 2080) identify opportunities and challenges to translate advances in basic and clinical neuroscience into novel medications to treat mood and anxiety disorders and schizophrenia. Some common themes emerge from these papers.…”