Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development

Abstract

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. These failures have raised serious concerns about the role of preclinical research in the identification and evaluation of new pharmacotherapies for psychiatry. In the absence of a comprehensive understanding of the neurobiology of psychiatric disorders, the task of developing “animal models” seems elusive. The purpose of this review is to highlight emerging strategies to enhance the utility of preclinical research in the drug development process. We address this issue by reviewing how advances in neuroscience, coupled with new conceptual approaches, have recently revolutionized the way we can diagnose and treat common psychiatric conditions. We discuss the implications of these new tools for modeling psychiatric conditions in animals and advocate for the use of systematic reviews of preclinical work as a prerequisite for conducting psychiatric clinical trials. We believe that work in animals is essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness.

Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents

“…A recent meta-analysis examined the effects of MS on anxiety-like behaviors such as exploratory-defensive behavior in rodents. Of note, meta-analyses are usually employed in clinical research to create evidence across various analyses, but are rarely performed in the context of animal studies [ 74 ]. The particular purposes of these meta-analyses are to measure the effect sizes of MS on exploratory-defensive behaviors using an open field test and an elevated plus maze test (the most commonly used tests to evaluate anxiety-like behaviors in rodents), as well as to determine their significance when compared to non-separated controls.…”

Systematic review and meta-analysis: effects of maternal separation on anxiety-like behavior in rodents

“…Exactly how adverse events early in life alter circuits that regulate anxiety and defensive behaviors is a difficult question to address in humans because of the inherent complexity of the adversities, genetic variability, and numerous additional variables that are difficult to control in clinical settings. Moreover, mechanistic studies that causally link structural and functional changes with alteration in anxiety or defensive responses are difficult, if not impossible, to conduct in humans 2,16 . In this regard, the conserved nature of defensive circuits between rodents and humans 15 suggests that animal models can provide important details about the mechanisms by which early adversity alters circuits that regulate defensive behaviors in humans.…”

“…To address these issues we conducted a systematic review and meta-analysis to examine the effects of MS on defensive-exploratory behavior in the OFT and EPM in mice and rats, two of the most commonly used anxietylike behavior tests in rodents 35 . Meta-analysis is an approach commonly used in clinical research to synthesize evidence across multiple studies but has been rarely used in the animal literature 16 . In fact, we are aware of only one meta-analysis examining the effects of MS on pain sensitivity in rodents 36 , and no other examples of meta-analyses assessing psychiatrically relevant outcomes such as defensive behavior, reward devaluation, or vulnerability to substance abuse.…”

Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning

“…Human imaging techniques, such as high-resolution MRI, dMRI, and rsfMRI, can be used in rodent models to characterize structural and functional outcomes that can be more directly compared to humans. Further, the contribution of structural and functional changes, measured via imaging, to behavioral alterations can be rigorously tested using optogenetics and chemogenetic tools ( Kaffman et al, 2019 ). Although rodents and non-human primates exposed to early life stress (ELS) show similar behavioral and physiological outcomes reported in human studies, the vast majority of work has been done only in males ( White and Kaffman, 2019b ; Bath, 2020 ).…”