Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP)

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group’s discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus - within the current protocols - the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression

Improving Translational Relevance in Preclinical Psychopharmacology (iTRIPP)

Animal models are important in preclinical psychopharmacology to study mechanisms and potential treatments for psychiatric disorders. A working group of 14 volunteers, comprising an international team of researchers from academia and industry, convened in 2021 to discuss how to improve the translational relevance and interpretation of findings from animal models that are used in preclinical psychopharmacology. The following paper distils the outcomes of the working group’s discussions into 10 key considerations for the planning and reporting of behavioural studies in animal models relevant to psychiatric disorders. These form the iTRIPP guidelines (Improving Translational Relevance In Preclinical Psychopharmacology). These guidelines reflect the key considerations that the group thinks will likely have substantial impact in terms of improving the translational relevance of behavioural studies in animal models that are used to study psychiatric disorders and their treatment. They are relevant to the research community when drafting and reviewing manuscripts, presentations and grant applications. The iTRIPP guidelines are intended to complement general recommendations for planning and reporting animal studies that have been published elsewhere, by enabling researchers to fully consider the most appropriate animal model for the research purpose and to interpret their findings appropriately. This in turn will increase the clinical benefit of such research and is therefore important not only for the scientific community but also for patients and the lay public

The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments

Most in vivo models of ischaemic stroke target the middle cerebral artery and a spectrum of stroke severities, from mild to substantial, can be achieved. This review describes opportunities to improve the in vivo modelling of ischaemic stroke and animal welfare. It provides a number of recommendations to minimise the level of severity in the most common rodent models of middle cerebral artery occlusion, while sustaining or improving the scientific outcomes. The recommendations cover basic requirements pre-surgery, selecting the most appropriate anaesthetic and analgesic regimen, as well as intraoperative and post-operative care. The aim is to provide support for researchers and animal care staff to refine their procedures and practices, and implement small incremental changes to improve the welfare of the animals used and to answer the scientific question under investigation. All recommendations are recapitulated in a summary poster (see supplementary information)

Endocrine and genetic moderation of serotonin systems and the psychopathology of affective disorders

The selective serotonin reuptake inhibitors (SSRIs) have taught us much about the pathophysiology of depression particularly about the impact that polymorphisms in the transporter gene seemed to have on susceptibility to depression have that seemed to explain the association between early life trauma and subsequent development of depression. Neuroimaging studies lent strong support for this hypothesis: finding a strong amplification of the activation of the amygdala in response to anger or fear-provoking stimuli in healthy short (S) allele carriers compared to those carrying the long (L) allele. Preclinical studies using transgenic animals carrying the S or L alleles, exposed to an SSRI in early life, suggested that amygdaloid reactivity is developmentally determined. The story is yet more complicated as further studies have identified a further 10 polymorphisms in the serotonin transporter whose functional consequences and interaction with environmental events are currently unknown.</p

The serotonin system:History, neuropharmacology, and pathology

The Serotonin System: History, Neuropharmacology, and Pathology provides an up-to-date accounting on the physiology and pathophysiology of serotonin and the role it plays in behavioral functions. In addition, the book explores the potential roles of 5-HT1 in neurodevelopmental disorders and summarizes the history of the discovery and development of serotonergic drugs for the treatment of neuropsychiatric disorders. This concise, yet thorough, volume is the perfect introduction to this critical neurotransmitter. It is ideal for students and researchers new to the study of behavior, neuropsychiatry or neuropharmacology, but is also a great resource for established investigators who want a greater perspective on serotonin.</p

The Possibilities and Limitations of Animal Models for Psychiatric Disorders

In the search for novel treatments for psychiatric disorders, many compounds that have shown promising pharmacological properties in disease models have failed to induce benefit in patients. There is good reason to believe that the preclinical approaches routinely used in drug discovery often provide an overly optimistic picture of clinical potential. Here we discuss some of the factors that we believe lead to erroneous decision-making, including: false interpretations of the behavioural significance of drug effects in the model species; fundamental flaws in aspects of experimental design and analysis; and misconceptions about the criteria that need to be applied before a model can be said to be validated. Only by focusing on well-constructed biological hypotheses of drug action in conjunction with reliable neurochemical, electrophysiological and behavioural assays that can be demonstrated to engage clinically relevant brain circuits will the chances of clinical success be improved. As psychiatric disorders come to be viewed less descriptively and more mechanistically as developmental disorders in brain circuits, incorporating biomarkers – measured biological variables that can indicate a normal or abnormal biological etiological process – will become the essential key to improving model development and validation, and target assessment and refinement.</jats:p