**1. Introduction**

According to the World Health Organization (WHO), psychiatric disorders (PDs) comprise a broad range of dysfunctions, with several and some common symptoms. PDs are generally characterized by the combination of symptoms as abnormal thoughts, emotions, behavior, and social interaction. The most common PDs include schizophrenia (SCZ), bipolar disorder (BD), major depression disorder (MDD), attention deficit hyperactivity disorder (ADHD), intellectual disabilities, drug abuse disorders, among others [1].

#### **1.1 The need and the value of animal models for PD studies**

There are several reasons to use animal models in the studies of disorders affecting the brain. The poor understanding of the etiopathogenesis and pathophysiology of PDs is clearly reflected by the unmet clinical need for better pharmacological

treatments. Therefore, good models are clearly needed to clarify the neurobiology involved in PDs, as well as for the identification of biomarkers useful to assist diagnosis and/or for the development of novel therapies. It is also implausible to move forward in clinical trials with a novel drug tested only in a cell model, without any evidence about its efficacy in animal experiments. The value of animal models to drug development has been demonstrated empirically. For example, the first and the most efficacious drugs available for complex PDs such as SCZ (e.g., chlorpromazine and clozapine) was discovered observing the alterations in behaviors of experimental animals in response to each drug administration. In fact, in the last decades, most of the CNS drugs approved were discovered employing a phenotypic screening approach in animal models [2, 3].

## **1.2 Challenges to model PDs in animals**

A reliable animal model must share several similarities with the studied target to allow a successful translation from the basic to the clinical research. However, several limitations need to be overcome. First, the heterogeneous behavioral symptom characteristics of PDs are in some grade uniquely expressed in humans, and they are certainly impossible to be reproduced authentically in animals as rodents, fishes or worms [4]. Second, there is a lack of an objective measure to unequivocally diagnose mental illness [5], which adds complexity to the modeling any mental disorder in experimental animals. Third, in order to develop meaningful animal models for PDs with potential translational power, the disease phenotypes must be represented in the experimental animals. The selection and update of these phenotypes, in agreement with the recent findings in clinical psychiatry and neuroscience, represents a challenge, as evidenced by the recognized gap between the clinical and basic scientific research [6]. In addition, a rising question is what are the specific traits or phenotypes that an animal model should express to be translatable to specific disorder? (**Figure 1**).

## **1.3 How to develop an animal model for PD studies**

The traditional approach to establish an animal model in PDs is based on three classic constructs proposed by Willner in 1984: face validity, which determines how much a phenotype presented by a patient is represented by the animal model (corresponds to similarity between the model and the PDs assessed, that includes symptoms, signs, and pharmacological features); construct validity, which demonstrates whether it is possible to reproduce the pathological condition based on processes that are already known to be altered (correspondence between the physiological dysfunctions in the human population and in the animal model); predictive validity, which tries to evaluate if a pharmacological or non-pharmacological intervention is capable to reverse the pathological condition (in other words, if the treatment that is effective in reversing PDs in humans would reverse the changes seen in animals) [7–10]. However, in practice, no animal models fully meet these three criteria of validity.

Many authors have proposed that instead of these three proposed criteria defining an external validation, in addition, the validity of an animal model should not be simply organisms that resemble human dysfunction, but they would also reproduce the processes by which animals and humans enter this state, and therefore, this could be better exploited by adding a new validation criteria [9]. For instance, the validity by homology, which proposes, for instance, an invertebrate model, such as *Drosophila*, may not be the ideal animal model for studying complex changes in a brain circuitry, but in turn, it may represent a great choice to study the genetic control of early embryonic development [11]. In fact, the nematode *Caenorhabditis elegans* is a reliable model with conserved neurobiological systems

**59**

**Figure 1.**

*Animal Models in Psychiatric Disorder Studies DOI: http://dx.doi.org/10.5772/intechopen.89034*

that has been helpful in the discovery of molecular mechanisms that underlie learning and memory, and, in addition, this animal model has a fully sequenced genome and other several molecular and genetic tools available for researchers [12, 13].

There is a consensus about the low reliability of the diagnostic construct provided for the employment of Diagnostic and Statistical Manual of Mental Disorders or DMS (which is a manual that determines the criteria for the clinical diagnosis of PDs). The heterogeneity implicit in this classification system and the imprecise quantification of the symptoms make it impossible to deconstruct PDs within model organisms. In fact, an etiology-based nosology system has been advocate for psychiatry, and it has been proposed to identify the endophenotypes that occur in both healthy individuals and subjects with different psychopathologies [14]. Endophenotypes are basically quantitative trait-like deficits that are possible to assess by laboratory-based methods rather than by clinical observation. An endophenotype should be state-independent, heritable, occurring at a high rate in affected families, and in addition, it should be associated to genetic variants of the disorder, as it should be involved the same brain

**1.4 Symptoms versus endophenotypes in experimental model animals**

*Different approaches to construct animal models for neuropsychiatric disorders studies.*

circuits associated with the symptoms of the illness in patients (**Table 1**).

The Research Domains Criteria (RDoC) framework was introduced as an alternative categorization system for psychopathological states [15–17]. This system provides a platform to improve the translatability of studies from animals to humans, since it supports the endophenotype-based comparison of animals and humans on an objective neurobiological basis across all behavioral domains. In fact, the endophenotypes have been reverse-translated into animal models successfully and allows the evaluation *Animal Models in Psychiatric Disorder Studies DOI: http://dx.doi.org/10.5772/intechopen.89034*

**Figure 1.**

*Animal Models in Medicine and Biology*

screening approach in animal models [2, 3].

**1.3 How to develop an animal model for PD studies**

**1.2 Challenges to model PDs in animals**

treatments. Therefore, good models are clearly needed to clarify the neurobiology involved in PDs, as well as for the identification of biomarkers useful to assist diagnosis and/or for the development of novel therapies. It is also implausible to move forward in clinical trials with a novel drug tested only in a cell model, without any evidence about its efficacy in animal experiments. The value of animal models to drug development has been demonstrated empirically. For example, the first and the most efficacious drugs available for complex PDs such as SCZ (e.g., chlorpromazine and clozapine) was discovered observing the alterations in behaviors of experimental animals in response to each drug administration. In fact, in the last decades, most of the CNS drugs approved were discovered employing a phenotypic

A reliable animal model must share several similarities with the studied target to allow a successful translation from the basic to the clinical research. However, several limitations need to be overcome. First, the heterogeneous behavioral symptom characteristics of PDs are in some grade uniquely expressed in humans, and they are certainly impossible to be reproduced authentically in animals as rodents, fishes or worms [4]. Second, there is a lack of an objective measure to unequivocally diagnose mental illness [5], which adds complexity to the modeling any mental disorder in experimental animals. Third, in order to develop meaningful animal models for PDs with potential translational power, the disease phenotypes must be represented in the experimental animals. The selection and update of these phenotypes, in agreement with the recent findings in clinical psychiatry and neuroscience, represents a challenge, as evidenced by the recognized gap between the clinical and basic scientific research [6]. In addition, a rising question is what are the specific traits or phenotypes that an animal model should express to be translatable to specific disorder? (**Figure 1**).

The traditional approach to establish an animal model in PDs is based on three classic constructs proposed by Willner in 1984: face validity, which determines how much a phenotype presented by a patient is represented by the animal model (corresponds to similarity between the model and the PDs assessed, that includes symptoms, signs, and pharmacological features); construct validity, which demonstrates whether it is possible to reproduce the pathological condition based on processes that are already known to be altered (correspondence between the physiological dysfunctions in the human population and in the animal model); predictive validity, which tries to evaluate if a pharmacological or non-pharmacological intervention is capable to reverse the pathological condition (in other words, if the treatment that is effective in reversing PDs in humans would reverse the changes seen in animals) [7–10]. However, in practice, no animal models fully meet these three criteria of validity. Many authors have proposed that instead of these three proposed criteria defining an external validation, in addition, the validity of an animal model should not be simply organisms that resemble human dysfunction, but they would also reproduce the processes by which animals and humans enter this state, and therefore, this could be better exploited by adding a new validation criteria [9]. For instance, the validity by homology, which proposes, for instance, an invertebrate model, such as *Drosophila*, may not be the ideal animal model for studying complex changes in a brain circuitry, but in turn, it may represent a great choice to study the genetic control of early embryonic development [11]. In fact, the nematode *Caenorhabditis elegans* is a reliable model with conserved neurobiological systems

**58**

*Different approaches to construct animal models for neuropsychiatric disorders studies.*

that has been helpful in the discovery of molecular mechanisms that underlie learning and memory, and, in addition, this animal model has a fully sequenced genome and other several molecular and genetic tools available for researchers [12, 13].
