Sleep disorders are very common in the modern society. In the United States it is calculated that between 50 and 70 million of people suffer from some kind of sleep disorder while it is estimated that in the developing countries across the world these conditions affect approx. 150 million people. Disorders of the sleep are on the rise worldwide and affect people of all ages, gender, and ethnicity. An inadequate sleep poor in quantity and quality and an excessive daytime sleepiness negatively affect daily activities causing, for example, poor concentration, memory difficulties, and impaired driving ability.
Given the magnitude and impact on the society, it is not surprising that there is an increasing interest by governments, universities, and media on sleep and sleep-related disorders. Several scientific societies such as The American Academy of Sleep Medicine, The National Sleep Foundation, and the Sleep Research Society have been established and disorders of sleep are now recognized as a separate medical subspecialty with specific training courses being offered in medical schools worldwide to prepare doctors to properly diagnose and treat these disorders.
The past decade has witnessed major advances in the understanding of sleep physiology and pharmacology which have provided a better understanding of the mechanisms that underlie sleep and have prompted promising research in this field which in turn have led to the development of new and better drugs to treat these conditions. The FDA has recently approved new drugs to treat disorders of sleep and other molecules are in advanced phase of clinical development or have just completed the development process. Furthermore, new regulatory and clinical guidelines for the development of drugs and treatment of these conditions have been issued or are in preparation.
The idea behind this book is to review some of the recent major breakthroughs in the drug treatment of sleep disorders. The drugs reviewed in the book, whether recently approved drugs (i.e., Doxepin), variations of previously approved molecules (i.e., Zolpidem sublingual preparation), or new chemical entities in late stage of clinical development (i.e., Lorediplon), have significantly changed or are expected to change the drug treatment of these disorders. Each chapter of the book was written by an expert in the field and is structured in such way that can be read as stand-alone chapter or as part of the whole book. The final result is a comprehensive yet practical book that will bring all the scientists, clinicians, and drug developers up to date in this area. Barcelona, Spain Antonio Guglietta August 2014

Part I General Concepts

An Overview of Sleep Physiology and Sleep Regulation 3

Neuronal Networks Regulating Sleep and Arousal: Effect of Drugs 25

Classification of Sleep Disorders 71

Development of New Therapeutical Agents for Treatment of Insomnia and Other Sleeps Disorders 85

Part II Drugs to Treat Insomnia

Low-Dose Doxepin for Insomnia 111

Lorediplon: A New GABA_A Modulator Drug for Treatment of Insomnia 121

Zolpidem Sublingual Formulations 147

Eszopiclone: Review and Clinical Applications in Chronic and Comorbid Insomnia 159

Orexin/Hypocretin Antagonists in Insomnia: From Bench to Clinic 191

Part III Drugs to Treat Excessive Daytime Sleepiness

Modafinil and Armodafinil 211

Sodium Oxybate (Xyrem~R): A New and Effective Treatment for Narcolepsy with Cataplexy 231

Cell Therapy to Treat Narcolepsy 249

Part IV Drugs to Treat Orcadian Sleep Disorders

Tasimelteon 261

Part V Conclusive Remarks

The Past, Present, and Future of Drug Development and Treatment in Sleep Disorders 273

Index 289

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