Introduction to the EQIPD quality system.

While high risk of failure is an inherent part of developing innovative therapies, it can be reduced by adherence to evidence-based rigorous research practices. Supported through the European Union's Innovative Medicines Initiative, the EQIPD consortium has developed a novel preclinical research quality system that can be applied in both public and private sectors and is free for anyone to use. The EQIPD Quality System was designed to be suited to boost innovation by ensuring the generation of robust and reliable preclinical data while being lean, effective and not becoming a burden that could negatively impact the freedom to explore scientific questions. EQIPD defines research quality as the extent to which research data are fit for their intended use. Fitness, in this context, is defined by the stakeholders, who are the scientists directly involved in the research, but also their funders, sponsors, publishers, research tool manufacturers, and collaboration partners such as peers in a multi-site research project. The essence of the EQIPD Quality System is the set of 18 core requirements that can be addressed flexibly, according to user-specific needs and following a user-defined trajectory. The EQIPD Quality System proposes guidance on expectations for quality-related measures, defines criteria for adequate processes (i.e. performance standards) and provides examples of how such measures can be developed and implemented. However, it does not prescribe any pre-determined solutions. EQIPD has also developed tools (for optional use) to support users in implementing the system and assessment services for those research units that successfully implement the quality system and seek formal accreditation. Building upon the feedback from users and continuous improvement, a sustainable EQIPD Quality System will ultimately serve the entire community of scientists conducting non-regulated preclinical research, by helping them generate reliable data that are fit for their intended use.

The preclinical data forum network: A new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience.

Current limitations impeding on data reproducibility are often poor statistical design, underpowered studies, lack of robust data, lack of methodological detail, biased reporting and lack of open data sharing, coupled with wrong research incentives. To improve data reproducibility, robustness and quality for brain disease research, a Preclinical Data Forum Network was formed under the umbrella of the European College of Neuropsychopharmacology (ECNP). The goal of this network, members of which met for the first time in October 2014, is to establish a forum to collaborate in precompetitive space, to exchange and develop best practices, and to bring together the members from academia, pharmaceutical industry, publishers, journal editors, funding organizations, public/private partnerships and non-profit advocacy organizations. To address the most pertinent issues identified by the Network, it was decided to establish a data sharing platform that allows open exchange of information in the area of preclinical neuroscience and to develop an educational scientific program. It is also planned to reach out to other organizations to align initiatives to enhance efficiency, and to initiate activities to improve the clinical relevance of preclinical data. Those Network activities should contribute to scientific rigor and lead to robust and relevant translational data. Here we provide a synopsis of the proceedings from the inaugural meeting.

Discovery and SAR of novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.

Removing obstacles in neuroscience drug discovery: the future path for animal models.

Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. To address these issues, this review critically discusses the traditional role of animal models in drug discovery, the difficulties encountered, and the reasons why this approach has led to suboptimal utilization of the information animal models provide. The discussion focuses on how animal models can contribute most effectively to translational medicine and drug discovery and the changes needed to increase the probability of achieving clinical benefit. Emphasis is placed on the need to improve the flow of information from the clinical/human domain to the preclinical domain and the benefits of using truly translational measures in both preclinical and clinical testing. Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. The purpose of this review is to strongly encourage ever more intensive clinical and preclinical interactions to ensure that basic science knowledge gained from improved animal models with good predictive and construct validity readily becomes available to the pharmaceutical industry and clinical researchers to benefit patients as quickly as possible.

IMPA1 is essential for embryonic development and lithium-like pilocarpine sensitivity.

Lithium has been the standard pharmacological treatment for bipolar disorder over the last 50 years; however, the molecular targets through which lithium exerts its therapeutic effects are still not defined. We characterized the phenotype of mice with a dysfunctional IMPA1 gene (IMPA1-/-) to study the in vivo physiological functions of IMPA1, in general, and more specifically its potential role as a molecular target in mediating lithium-dependent physiological effects. Homozygote IMPA1-/- mice died in utero between days 9.5 and 10.5 post coitum (p.c.) demonstrating the importance of IMPA1 in early embryonic development. Intriguingly, the embryonic lethality could be reversed by myo-inositol supplementation via the pregnant mothers. In brains of adult IMPA1-/- mice, IMPase activity levels were found to be reduced (up to 65% in hippocampus); however, inositol levels were not found to be altered. Behavioral analysis of the IMPA1-/- mice indicated an increased motor activity in both the open-field test and the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures, the latter supporting the idea that IMPA1 represents a physiologically relevant target for lithium. In conclusion the IMPA1-/- mouse represents a novel model to study inositol homeostasis, and indicates that genetic inactivation of IMPA1 can mimic some actions of lithium.

Lack of lithium-like behavioral and molecular effects in IMPA2 knockout mice.

Lithium is a potent mood-stabilizing medication in bipolar disorder. Despite 50 years of clinical use, the mechanism of action is unknown. Multiple effects have been attributed to lithium including the uncompetitive inhibition of inositol monophosphatase (IMPase). IMPA2, one of the genes that encode IMPase, is located in a region with linkage to bipolar disorder. Owing to the role of IMPase in cell signaling and the possibility that this enzyme is a target for mood-stabilizing drugs, we generated IMPA2(-/-) mice. Possible involvement of IMPase in complex behaviors related to affective disorders was assessed by monitoring the behavior of the IMPA2(-/-) mice in the forced swim test, the tail suspension test (TST), the elevated zero-maze and open field test. It has been described that chronically lithium-treated mice exhibit reduced immobility time in the forced swim test and decreased exploratory behavior. We found increased rearing of IMPA2(-/-) mice in the open field, suggesting an increased exploratory behavior. Although immobility time of IMPA2(-/-) female but not male mice in the forced swim test was reduced, no difference was found between male and female IMPA2(-/-) and IMPA2(+/+) mice in the TST and overall there was no clear effect of the deletion of IMPA2 on depression-like behavior. Frontal cortex IMPase activity and inositol levels in the IMPA2(-/-) mice did not differ from IMPA2(+/+) mice, but kidney inositol levels were reduced. In conclusion, phenotypic characterization of the IMPA2(-/-) mouse indicates that deleting IMPA2 does not mimic the effects of lithium treatment.

Behavioral testing of antidepressant compounds: an analysis of crossover design for correlated binary data.

The differential reinforcement of low-rate 72 seconds schedule (DRL-72) is a standard behavioral test procedure for screening potential antidepressant compounds. The protocol for the DRL-72 experiment, proposed by Evenden et al. (1993), consists of using a crossover design for the experiment and one-way ANOVA for the statistical analysis. In this paper we discuss the choice of several crossover designs for the DRL-72 experiment and propose to estimate the treatment effects using either generalized linear mixed models (GLMM) or generalized estimating equation (GEE) models for clustered binary data.