What is an animal model of a neuropsychiatric disorder?

1.1 Introduction

Neuropsychiatric disorders are conditions that have a significant and sometimes devastating impact on a large proportion of the human population. Mental health surveys carried out in the United States suggest that during any 1-year period, approximately 26% of the population will have a mental disorder, and almost 50% of all people will have mental illness sometime during their lifetime. Yearly, approximately 6% of the population experiences a very serious mental illness that involves a suicide attempt, significant work disability, or repeated serious violent behavior (Kessler et al., 2005). Yet, the currently available treatments for these mental illnesses are less than adequate. In the case of major depressive disorder, for example, the typical first-line pharmacotherapy, a 12-week treatment with a selective serotonin reuptake inhibitor, results in remission (complete or almost complete absence of symptoms) for approximately 30–50% of cases, and only 20–30% of people that do not respond to the first-line treatment will remit within 12 weeks of receiving an alternative pharmacologic treatment (Rush et al., 2006). Psychotherapy (without drug treatment) results in almost identical remission rates for major depressive disorder (Cuijpers et al., 2013). Similarly, the typical and atypical antipsychotics currently used to treat schizophrenia are mostly effective for a subset of schizophrenic symptoms (hallucinations, delusions, the so-called “positive” symptoms) while cognitive and negative symptoms (deficits in working memory and attention, negative affect, and anhedonia) remain mostly unresponsive to current pharmacologic therapies. Therefore, there is a strong motivation for understanding the biologic roots of these disorders, in order to develop new, potentially more effective treatments that are specifically targeted to correcting the relevant pathophysiologic mechanisms. Understanding the pathophysiology of neuropsychiatric disorders is challenging due to the inherent complexity of the human brain and the limited types of experimental methodologies that can be applied in human studies: there are obvious ethical constraints on the study of humans, and it is practically impossible to control for many important variables. These problems in part can be overcome through the study of nonhuman subjects, and a major research effort has focused on developing so-called “animal models” of human neuropsychiatric conditions. However, this effort has not been without its skeptics and critics, who justifiably question whether syndromes so complex—and so human—as schizophrenia and depression (just to name two examples) can really be observed and replicated in animals. So, what exactly constitutes an animal model of a neuropsychiatric disorder? The current chapter will explore this question, but first, it is necessary to start with a more basic question, that is, what is—and what is not—a neuropsychiatric disorder?

1.2 What is a neuropsychiatric disorder? (and what is not?)

This may seem as an odd place to start, but if an experimental paradigm is meant to model a neuropsychiatric disorder, then it is important to be clear on what exactly is meant by this term. And, as it turns out, the question is more difficult to answer than it might appear to be. Although the terms “disease” and “disorder” are often used interchangeably, a distinction is sometimes made between them: while both terms refer to “an abnormality or medical condition that confers harm or risk of harm” (Hyman, 2010), the term “disease” can imply that the etiology of the condition is known, whereas “disorder” is often taken to imply that underlying causal factors have not yet been identified. In the present context, the adjective “neuropsychiatric” could equally well be replaced by “psychiatric” or “mental,” but the term “neuropsychiatric” emphasizes that these disorders are assumed to have clear biologic roots that lie within the function of the nervous system.

Neuropsychiatric disorders are currently diagnosed and classified based on the systems outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V, American Psychiatric Association, 2013) or in the International Classification of Diseases, Tenth Revision (ICD-10, World Health Organization, 1992). Due to a growing appreciation of the diversity and complexity of neuropsychiatric disorders, the systems for diagnosing and classifying these conditions have evolved. While original classification schemes attempted to define individual neuropsychiatric disorders as conditions distinct both from the healthy state and from each other, current conceptualizations of psychopathology recognize the presence of considerable comorbidity of supposedly distinct disorders, as well as significant symptom sharing among them. To illustrate, in one survey on comorbidity of neuropsychiatric disorders (Kessler et al., 2005), almost half of those survey participants that had suffered from mental illness were diagnosed with two or more DSM-defined disorders. Moreover, it has become increasingly clear that many neuropsychiatric symptoms are represented in an attenuated form or at nonpathologic levels in individuals in the general population. As a step toward a more dimensional (and realistic) classification of psychopathology, DSM-V has regrouped categorically defined disorders into diagnostic categories (represented as individual chapters) based on certain validating criteria, including: (1) the presence of similar genetic markers, familial traits, temperament, and exposure to specific environmental conditions, or “antecedent validators”; (2) similarity of symptoms and emotional and cognitive processing, as well as similarity in the presence of biomarkers or neural substrates, or “concurrent validators”; and (3) “predictive validators,” which include similarities among disorders with respect to clinical course and treatment response. At present, given the relative paucity of information on the etiology of most neuropsychiatric disorders, similarities among disorders in their clinical course and treatment response remain the most clinically useful manner to define diagnostic categories.

DSM-V defines a mental disorder as “…a syndrome characterized by clinically significant disturbance in an individual’s cognition, emotion regulation, or behavior that reflects a dysfunction in the psychological, biologic, or developmental processes underlying mental functioning … usually associated with significant distress or disability in social, occupational, or other important activities…” Emotional states that are culturally and contextually appropriate, such as the sadness experienced in response to the loss of a loved one or the relatively mild feelings of anxiety...