Predictive Validity Of Animal Models Research Articles

Using neurocognitive models to optimise the treatment of depression

AbstractConventional antidepressants, such as SSRIs, are an effective treatment for many patients with depression. However, for a significant proportion of patients SSRIs either lack efficacy or are poorly tolerated. Even when SSRIs are effective in treating mood symptoms, there are often residual symptoms that are not well treated, including cognitive impairment and anhedonia. The development of novel treatment for depression is particularly challenging given the limited predictive validity of animal models. Human neurocognitive models of antidepressant action can help to bridge the translational gap and allow rapid investigation of novel compounds in healthy volunteers and people with depression. In this talk, using the 5-HT4 receptor as an example of a novel target of interest, I will outline how these objective neurocognitive models can be used as a translational tool to understand antidepressant treatment mechanisms, guide treatment selection and test novel putative antidepressants early in development.Disclosure of InterestS. Murphy Grant / Research support from: Zogenix, UCB, Janssen, Consultant of: Zogenix, Sumitomo Danippon, Janssen, UCB, Speakers bureau of: Zogenix

Animal models of pain: Diversity and benefits

Chronic pain is a maladaptive neurological disease that remains a major health problem. A deepening of our knowledge on mechanisms that cause pain is a prerequisite to developing novel treatments. A large variety of animal models of pain has been developed that recapitulate the diverse symptoms of different pain pathologies. These models reproduce different pain phenotypes and remain necessary to examine the multidimensional aspects of pain and understand the cellular and molecular basis underlying pain conditions.In this review, we propose an overview of animal models, from simple organisms to rodents and non-human primates and the specific traits of pain pathologies they model. We present the main behavioral tests for assessing pain and investing the underpinning mechanisms of chronic pathological pain. The validity of animal models is analysed based on their ability to mimic human clinical diseases and to predict treatment outcomes. Refine characterization of pathological phenotypes also requires to consider pain globally using specific procedures dedicated to study emotional comorbidities of pain. We discuss the limitations of pain models when research findings fail to be translated from animal models to human clinics. But we also point to some recent successes in analgesic drug development that highlight strategies for improving the predictive validity of animal models of pain. Finally, we emphasize the importance of using assortments of preclinical pain models to identify pain subtype mechanisms, and to foster the development of better analgesics.

Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development.

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.

Chapter 2 - Animal models of cognitive aging and circuit-specific vulnerability

Medial temporal lobe and prefrontal cortical structures are particularly vulnerable to dysfunction in advanced age and neurodegenerative diseases. This review focuses on cognitive aging studies in animals to illustrate the important aspects of the animal model paradigm for investigation of age-related memory and executive function loss. Particular attention is paid to the discussion of the face, construct, and predictive validity of animal models for determining the possible mechanisms of regional vulnerability in aging and for identifying novel therapeutic strategies. Aging is associated with a host of regionally specific neurobiologic alterations. Thus, targeted interventions that restore normal activity in one brain region may exacerbate aberrant activity in another, hindering the restoration of function at the behavioral level. As such, interventions that target the optimization of "cognitive networks" rather than discrete brain regions may be more effective for improving functional outcomes in the elderly.

Estimating the predictive validity of diabetic animal models in rosiglitazone studies.

For therapeutic studies, predictive validity of animal models - arguably the most important feature of animal models in terms of human relevance - can be calculated retrospectively by obtaining data on treatment efficacy from human and animal trials. Using rosiglitazone as a case study, we aim to determine the predictive validity of animal models of diabetes, by analysing which models perform most similarly to humans during rosiglitazone treatment in terms of changes in standard diabetes diagnosis parameters (glycosylated haemoglobin [HbA1c] and fasting glucose levels). A further objective of this paper was to explore the impact of four covariates on the predictive capacity: (i) diabetes induction method; (ii) drug administration route; (iii) sex of animals and (iv) diet during the experiments. Despite the variable consistency of animal species-based models with the human reference for glucose and HbA1c treatment effects, our results show that glucose and HbA1c treatment effects in rats agreed better with the expected values based on human data than in other species. Induction method was also found to be a substantial factor affecting animal model performance. The study concluded that regular reassessment of animal models can help to identify human relevance of each model and adapt research design for actual research goals.

FDG–PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease

The lack of reliable translational procedures applicable to both patients and experimental models are a major obstacle for the advancement of basic research as well as for the development of therapeutics. This is particularly relevant to neurodegenerative disorders such as AD (Alzheimer's disease), where the predictive validity of animal models and procedures applied preclinically have met with little success. Two approaches available for human diagnostics are currently experiencing major advancements in preclinical research: in vivo imaging using MRI (magnetic resonance imaging) or PET (positron-emission tomography) and recordings of brain electrical activity via surface EEG (electroencephalogram). The present paper reviews the results obtained so far in rodent AD models, and summarizes advantages and disadvantages of such procedures.

S.15.03 Combined effect of antidepressant and anti-inflammatory drugs in an animal model of depression

Over the course of the last 50 years many models of major depressive disorder have been developed on the basis of theoretical aspects of this disorder. These models and procedures have been crucial in the discovery and development of clinically-effective drugs. Notwithstanding, there is presently great concern about the discrepancy between positive outcomes of new candidate drugs in animal models and apparent lack of efficacy in humans i.e., the predictive validity of animal models. Some reasons for this concern lie in the over-reliance in the face value of behavioural models, design of clinical trials, placebo responses, genetic variations in response to drugs, species differences in bioavailability and toxicology, and not least, disinterest of pharmaceutical sponsors to continue developing certain drugs. Present model development is focusing on endophenotypic aspects of behaviours rather than trying to model whole syndromes. This essay traces the origins and theoretical bases of our animal models of depression or depressed-like behaviours in humans and indicates how they have evolved from behavioural assays used to measure the potency and efficacy of potential candidate drugs to tools by which endophenotypes of depression may be identified and verified pharmacologically. A cautionary note is included though to indicate that the true predictive validity of our models will not be fully assessed until we can determine the attrition rate of molecules discovered from new drug targets translating into clinically-effective drugs.

Animal models of depression in drug discovery: A historical perspective

Over the course of the last 50 years many models of major depressive disorder have been developed on the basis of theoretical aspects of this disorder. These models and procedures have been crucial in the discovery and development of clinically-effective drugs. Notwithstanding, there is presently great concern about the discrepancy between positive outcomes of new candidate drugs in animal models and apparent lack of efficacy in humans i.e., the predictive validity of animal models. Some reasons for this concern lie in the over-reliance in the face value of behavioural models, design of clinical trials, placebo responses, genetic variations in response to drugs, species differences in bioavailability and toxicology, and not least, disinterest of pharmaceutical sponsors to continue developing certain drugs. Present model development is focusing on endophenotypic aspects of behaviours rather than trying to model whole syndromes. This essay traces the origins and theoretical bases of our animal models of depression or depressed-like behaviours in humans and indicates how they have evolved from behavioural assays used to measure the potency and efficacy of potential candidate drugs to tools by which endophenotypes of depression may be identified and verified pharmacologically. A cautionary note is included though to indicate that the true predictive validity of our models will not be fully assessed until we can determine the attrition rate of molecules discovered from new drug targets translating into clinically-effective drugs.

Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts

Recommendations from experts and recently established guidelines on how to improve the face and predictive validity of animal models of stroke have stressed the importance of using older animals and long-term behavioral-functional endpoints rather than relying almost exclusively on acute measures of infarct volume in young animals. The objective of the present study was to determine whether we could produce occlusions in older rats with an acceptable mortality rate and then detect reliable, long-lasting functional deficits. A reversible intraluminar suture middle cerebral artery occlusion (MCAO) procedure was used to produce small infarcts in middle-aged rats. This resulted in an acceptable mortality rate, and robust disabilities were detected in functional assays, although the degree of total tissue loss measured 90 d after MCAO was quite modest. Infarcted animals were functionally impaired relative to sham control animals even 90 d after the occlusions, and when animals were subgrouped based on amount of tissue loss, MCAO animals with only 4% tissue loss exhibited enduring neurological-behavioral impairments relative to sham-operated controls, and the functional impairments in the group with the largest infarcts (20% tissue loss) were more severe than the functional impairments in the rats with 4% tissue loss. These results suggest that this model, using reversible MCAO to produce small infarcts and long-lasting functional-behavioral deficits in older rats, may represent an advance in the relatively higher-throughput modeling of stroke and its recovery in rodents and may be useful in the development and characterization of future stroke therapies.

A Test of the Predictive Validity of Animal Models of Schizophrenia Based on Phencyclidine and D-Amphetamine

Antipsychotic drugs can inhibit the effects of phencyclidine (PCP) and d-amphetamine (AMPH) in many rodent tests, but the effects are usually seen at doses that also affect vehicle-treated control rats, suggesting that the inhibition may be nonspecific. This study will attempt to test the predictive validity of these models based on the clinical observations that antipsychotics are not fully effective until after 2–3 weeks of administration in patients and that patients do not relapse immediately following abrupt withdrawal of medication. Haloperidol and clozapine were tested in rats after daily administration for 3 and 21 days in combination with vehicle or PCP (2.0 mg/kg) in the social interaction test, and with vehicle or AMPH (0.5 mg/kg) in standard activity cages. To separate acute from more long-lasting effects on the central nervous system (CNS) haloperidol and clozapine were tested with a short (45 or 30 min depending upon test) and a long (22–24 h) pretreatment time. The results demonstrated that haloperidol and clozapine following both 3 and 21 days of administration at the short pretreatment time inhibited the activity of vehicle-, PCP-, and AMPH-treated rats, whereas neither drug had consistent effects in any group at the long pre-treatment time. The data suggest that antipsychotics only inhibit PCP- and AMPH-induced behaviors in rodents by an acute drug-drug interaction, whereas any long-term effects of antipsychotic drug administration on the CNS cannot be revealed by PCP and AMPH in rodents.

Animal models of dementia

AbstractThe major use of animal models for dementia is in the development of new therapeutic drugs. In contrast to other areas in psychopharmacology, where the predictive validity of animal models can be established by examining their response to known therapeutic agents, the search for antidementia drugs is hampered by the absence of recognized clinically effective reference compounds. Research scientists are therefore obliged to validate their models in terms of their similarity to the clinical condition. A second problem is the therapeutic target. Although antidementia drugs are intended to improve cognition in a general sense, the foremost therapeutic targets are the deficits in memory and attention associated with aging. The aging animal would appear to represent the best available model providing it can be shown that the cognitive deficits observed are similar to those observed in old age in humans. A logical consequence of this approach is to validate other experimental models in terms of their resemblance to naturally occurring age‐related impairments.To illustrate these points, this paper reviews data obtained in aging animals in various behavioral models and the effects of drugs thereon. Comparisons are made between drug effects in aged animals with those observed in experimental models in young animals in which cognitive deficits are induced by anticholinergic drug treatment or lesions to cholinergic‐rich brain regions. It is concluded that aging induces cognitive deficits mainly associated with short‐term memory but that other aspects of cognition, namely attention and information processing speed, also decline with age. Putative antidementia drugs, particularly those facilitating cholinergic transmission, appear frequently to have more marked effects in experimental deficit models than in aged animals themselves. © 1995 Wiley‐Liss, Inc.