Alcohol abuse and dependence are the third highest risk to health in developing countries and cause 3.2% of deaths worldwide. There are certain characteristics of alcohol dependence that are of clinical importance, but are seen to a lesser extent with nicotine dependence, though some of these are also features of dependence on opiates or psycho stimulant drugs. A large proportion of alcoholics suffer from other serious psychiatric disorders, many are malnourished, suffering in particular from thiamine deficiency, and have unhealthy diets; 50 to 80% of alcoholics have cognitive deficits and these deficits not only affect the quality of life of alcoholics and the amount of health care they need, but also have a detrimental effect on their ability to benefit from current treatment programs. The effects of long-term alcohol consumption on memory also need to be considered in the context of animal models. Multidrug use is a problem with all types of dependence, including alcohol, but animal models of alcohol dependence have tended to avoid that particular complication. The main animal models in current use for testing drugs for the treatment of alcohol dependence, voluntary drinking and operant self-administration have demonstrated effects of the treatments in current use, but have also shown positive results with compounds that have not proved of value in humans. This chapter discusses some current treatment of alcohol dependence, approaches to the treatment of alcohol dependence, behavioral models of alcohol dependence, and correspondence of efficacy of established and novel treatments for alcohol dependence in animals and humans.

Depression is, according to the World Health Organization, among the top five causes of disability and is a major healthcare problem and thus a serious economic burden for society. Current treatments for depression and anxiety disorders are of limited efficacy in many patients and are associated with side effects that reduce compliance in others. As all antidepressants currently used exert their primary pharmacological action by altering serotonergic and/or noradrenergic pathways in the brain, substantial research efforts have been directed toward the potential to develop novel, more effective, non-monoamine-based antidepressant medications. To date, this has proved very difficult and along the way there have been a number of high-profile casualties, most notably the Neurokinin (NK)-1 receptor antagonists, which demonstrated an excellent preclinical portfolio but failed in clinical trials. All of the present preclinical tests available in depression research were developed after the clinical introduction of the first generation of antidepressants, the Tricyclic Antidepressants (TCAs), and monoamine oxidase inhibitors and are more appropriately viewed as tests predictive of antidepressant-activity, or even more reductionistically, as tests of enhanced monoamine function. There is a shift away from these traditional animal models to more focused research dealing with an endophenotype-style approach, selective breeding programs and incorporation of new findings from human neuroimaging and genetic studies. Moreover, advances in neuroimaging and in biomarker development also inform the clinical testing of novel drugs. This chapter assesses these new directions and the potential impact that they could have in developing novel therapeutics for depression where there is a huge unmet medical need.

This chapter discusses government's outlook in the drug discovery and development for reward disorders. The National Institute on Drug Abuse (NIDA) is the world's largest research institution dedicated to funding research on drugs of abuse, prevention of drug abuse, and treatment of substance abuse disorders. The Division of Pharmacotherapies and Medical Consequences of Drug Abuse (DPMC) initiated a discovery and development program in 1990. The initial program intended to perform standardized tests and clinical studies to facilitate the discovery and development of addiction medications and to facilitate the involvement of the pharmaceutical industry and academia. The primary objective of this discovery program was to discover putative medications for the treatment of cocaine dependence. The structure, objectives, and testing scheme of the NIDA drug discovery programs have changed as a result of the maturing of the science and efforts to improve efficiency. Medication targets have expanded and relapse prevention has become the number one focus. The motivation for Federal involvement in the development of medications for the treatment of addictive disorders is from a public health viewpoint. They are heavily invested in the treatment of addictive disorders and views new medications to treat these disorders as a way to expand treatment and improve the public health of the United States.

In the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), Iimpulse Control Disorders (ICDs) are grouped as a heterogeneous cluster of disorders linked by a “failure to resist” impulses to engage in harmful, disturbing or distressing behaviors. The formal group of ICDs includes Pathological Gambling (PG), Intermittent Explosive Disorder (IED), kleptomania, pyromania, trichotillomania, and ICDs not otherwise specified. Criteria for other ICDs have been proposed including compulsive sexual behavior, compulsive shopping, compulsive skin picking, and compulsive computer use. ICDs have been conceptualized as “obsessive–compulsive spectrum disorders” and “behavioral addictions.” They have core clinical features including: (1) compulsive and repetitive performance of the problematic behavior despite adverse consequences; (2) loss of control over the behavior; (3) an appetitive urge or “craving” state before starting the behavior; and (4) a pleasurable quality associated with its performance. Despite relatively high prevalence rates in the general population and in psychiatric cohorts, ICDs have been relatively understudied. Controlled treatment trials have not been performed for many ICDs. This chapter reviews data on the neurobiology and treatment of ICDs including PG, trichotillomania, compulsive buying, IED, and kleptomania.

Schizophrenia is typically a lifelong and often devastating, but relatively common (life-time risk of 1%), psychiatric disorder, which often begins in late adolescence or early adulthood. This chapter reviews the current drug treatments for schizophrenia, the outstanding unmet needs for patients, the current understanding of the neurobiology of schizophrenia, and strategies for drug discovery. It focuses particularly on the development of appropriate animal models and translational approaches to aid in the understanding of the neurobiology of schizophrenia and to investigate the potential efficacy of novel pharmacological approaches. It discusses the challenges in drug discovery from both a preclinical and clinical perspective and examines the exciting advances in the understanding of this disorder and the various Academic/Government/Industry initiatives that are likely to make a major impact upon drug discovery in this area. It also considers some approaches that exemplify novel strategies for drug discovery or clinical investigation that promise significant advances in this field. The collaborative spirit needs to continue to focus the attention upon approaches that may improve the treatment of this debilitating and multi-syndromal disease.

Learning Disabilities (LD) affect approximately 15% of the US population, but currently there are no generally effective therapies for this class of cognitive disorders. To address this problem, it has been initially focused on Neurofibromatosis type I (NF1), a single gene disorder associated with learning disabilities. Previous studies showed that mice with a heterozygous null mutation of the NF1 gene have behavioral deficits related to the cognitive phenotype of NF1 patients. Studies of these mice showed increased Ras/MAPK signaling in the hippocampus and prefrontal cortex, which results in the upregulation of GABA release underlying the spatial, attention and working memory deficits of the mutants. Statins can be used to decrease the isoprenylation; therefore, the activity of Ras. Recent results demonstrate that a short treatment with statins, which is ineffective in controls, can reverse the increases in Ras-MAPK signaling, the synaptic plasticity, attention, and spatial learning deficits of the NF1 mutant mice. To test whether statins can also reverse the neurological and cognitive deficits associated with NF1 in patients, a series of collaborative pilot clinical studies in children and adults with NF1 has been initiated. These studies will not only have an impact on the understanding of cognitive deficits associated with NF1, it will also serve as a case study for how to investigate and treat learning disabilities.

Parkinson's Disease (PD) is the second most common, age-related progressive neurodegenerative disorder. Two events have impacted significantly the discovery and development approaches for novel therapeutics for PD: (a) the discovery of disease-causing mutations in multiple genes and (b) an emerging appreciation that the pathophysiology and associated symptoms of PD are more widespread than those resulting from the progressive loss of the nigrostriatal dopamine projections. Specifically, there has been an emergence of new animal models based on genetic etiology of familial PD and hence a renewed focus on using the new animal models to develop therapeutic strategies aimed at slowing the progression of the disease as well as treating non-motor symptoms of PD. This chapter provides an overview of the current state of the PD research with a special emphasis on animal models that can help therapeutic discovery and development. It focuses on the animal models of disease pathophysiology and resultant symptoms. It presents a summary on the clinical syndrome and current therapies of PD to set the context for the discussion to follow on commonly used animal models, their phenotypes and how they correlate/reproduce disease pathophysiology or specific symptoms of PD. It also addresses the specific utility of animal models in drug discovery and development, paying attention to current challenges or gaps that hinder discovery and development of drugs addressing the unmet medical needs of PD patients. Additionally, the chapter offers some suggestions on the utility of classical animal models as well as emerging models to address these gaps and facilitate development of therapeutic interventions.

Clinical trials are conducted to determine the therapeutic efficacy, effectiveness, safety, and tolerability of interventions for clinical disorders. The best clinical trials are designed to do this efficiently with minimal potential for bias. This chapter focuses on the clinical trials of pharmacological interventions for psychiatric disorders, in particular, how translational models can improve the quality of these trials. The implementation of clinical trials is fraught with hazard. Present methods are incapable of assuring that the best patients are included in trials and that the true effects of assigned treatments are consistently captured. Inference making should be cautious and restrained. Only after multiple trials are completed by several groups of investigators using differing methodologies produce concordant results whether it should be believed that the findings are well supported and are to be used in the practice. As the back and forth process of developing translational models of pathophysiology and pharmacological actions in laboratory and clinical settings proceeds, clinical trials will become more objective and this will hasten the development of clinically useful medicines. Re-engaging dedicated clinical investigators will enhance the quality of this process.

This chapter focuses on the animal and translational models of neurological disorders and presents an industrial perspective. Recent advances in biomedical technology, in genetics, translational science and in experimental medicine offer real promise that this situation is about to change. Such a change will ultimately offer real benefits for patients with serious neurological conditions that currently have few treatment options. There are very few true animal models of neurological disease – that is, ones that are identical in cause, pathology and symptomatology – although much time, effort and money has been spent by behavioral scientists trying to develop these. These limited animal models actually were quite successful in developing symptomatic therapies, for example, sodium channel blockers for epilepsy, dopamine D2 receptor agonists for Parkinson's Disease (PD) and cholinesterase inhibitors for Alzheimer's Dementia (AD). Animal models will continue to be very valuable for screening for the unwanted effects of potential neurological medicines. Both experimental medicine and translational science, if applied and executed appropriately, have the potential to make a real impact on neurological drug discovery. If the important advances in technology, genetics, translational science and experimental medicine are to be of value to patients, more work needs to be done to move them from confidence building tools to end-points acceptable to regulatory bodies. There is a need for companies to work together in a precompetitive manner with the regulatory agencies to establish a framework for accelerating the utility of these biomarkers. This need has been recognized in a number of ongoing or proposed precompetitive initiatives in the United States of America, Europe and Asia-Pacific. Some of these initiatives are listed in the chapter.

Drug addiction, and in particular cocaine and heroin addiction, represents a terrible social burden and public health issue due to its high incidence among the youth, poor treatment outcomes, and high rate of relapse. The limited number of medications approved for the treatment of heroin dependence and the lack of medications approved for the treatment of cocaine dependence suggest many obstacles that must be overcome in developing drug treatments for these indications. Beyond the inherent difficulty of translating preclinical data into clinical efficacy, the development of medications for heroin and cocaine dependence provides some unique challenges, among them attenuating the clinical features of both acute and chronic drug intoxication that may involve—to varying extents in different individuals—drug-induced tolerance and physical dependence. This chapter focuses on the clinical aspects of heroin and cocaine dependence and the types of preclinical assays that can be used to study the abuse-related effects of these drugs. It discusses the information that has been obtained with these behavioral methodologies in two contexts of drug discovery: (1) the assessment of medications to treat heroin and cocaine addiction and (2) the assessment of the abuse liability of compounds in development for indications other than drug addiction. It also provides a brief overview of the current regulatory environment to illustrate the increasing importance of assessing abuse liability during drug development, and consequently the industry's obligations in limiting drug abuse liability.