The mouse as a model for neuropsychiatric drug development

Abstract

Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species' neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.

The impact of RASopathy-associated mutations on CNS development in mice and humans

“…Lastly, it should be noted that most of the RASopathy mechanism studies have used mice as a model system. Mouse models have many advantages and can be used to study neuropsychiatric disorders because the majority of neuropsychiatric drugs used in humans were shown to be, at least partially, effective in mouse models [218]. However, caution is still warranted.…”

A New Paradigm for Training Hyperactive Dopamine Transporter Knockout Rats: Influence of Novel Stimuli on Object Recognition

“…Furthermore, since DA is involved in various aspects of motivational behaviors and psychotic states (Efimova et al, 2016;Howe et al, 2018), the abnormal behaviors of DAT-KO animals may have relevance also for endophenotypes of other psychiatric disorders such as schizophrenia, bipolar disorder, autism, mania, obsessive-compulsive disorder, and addiction disorders (Arime et al, 2012;Wong et al, 2012;Jones et al, 2015;Mereu et al, 2017;Weinstein et al, 2017;Chang et al, 2018;Cinque et al, 2018;Chao et al, 2020). The DAT-KO rats might have good translational value for developing new treatment principles for mental disorders.…”

Phenotypic Differences between the Alzheimer’s Disease-Related hAPP-J20 Model and HeterozygousZbtb20Knock-Out Mice

“…However, these models may not be able to reliably predict the efficacy of therapeutic interventions in the human condition, in which multiple pathogenic factors act in concert. Negative preclinical drug trials that fail to reduce brain dysfunctions in such AD-relevant models should be taken seriously, however, because drugs that fail in a reductionist system would seem unlikely to succeed in a highly heterogeneous AD population, particularly since many neurotropic drugs with well-established efficacy in other human disorders back-translate rather well into related mouse models ( Howe et al, 2018 ). Notably, even early treatment of hAPP-J20 mice with a BACE1 inhibitor did not prevent their network dysfunction or cognitive decline, although this intervention prevented the formation of amyloid plaques, as well as plaque associated microgliosis, and markedly reduced Aβ oligomer levels in brain tissues ( Johnson et al, 2020 ).…”