Drugs for Insomnia beyond Benzodiazepines:...

1521-0081/70/2/197–245$35.00 https://doi.org/10.1124/pr.117.014381PHARMACOLOGICAL REVIEWS Pharmacol Rev 70:197–245, April 2018Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics

ASSOCIATE EDITOR: ERIC L. BARKER

Drugs for Insomnia beyond Benzodiazepines:Pharmacology, Clinical Applications, and Discovery

Tobias Atkin, Stefano Comai, and Gabriella Gobbi

Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University Health Center, McGill University, Montreal, Quebec, Canada(T.A., S.C., G.G.); and Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy (S.C.)

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200

A. Insomnia as a Public Health Burden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200B. Changes in the Nosology of Insomnia in Diagnostic and Statistical Manual of Mental

Disorders-V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200C. Clinical Guidelines for Insomnia Treatment and the Necessity of a Translational

Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200D. The Dark Side of Benzodiazepines and Z-Drugs and the Off-Label Use of Other Drugs . . 201

II. Sleep Architecture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201III. The Receptor-Mediated Mechanism of Action of Hypnotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

A. GABA Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202B. Serotonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202C. Serotonin 2 Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203D. Serotonin 1A Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203E. Noradrenaline Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203F. Dopamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204G. Orexin Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205H. Melatonin Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205I. Histamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206J. Other Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206K. From Receptors to Sleep Circuits. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

IV. Melatonergic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208A. Agomelatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

1. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2082. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2083. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2094. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2095. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2096. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

B. Prolonged-Release Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2092. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2093. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2094. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2095. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

Address correspondence to: Gabriella Gobbi, Neurobiological Psychiatry Unit, Department of Psychiatry, Ludmer Research andTraining Building, 1033, Avenue des Pins Ouest, Montreal, Quebec, Canada H3A 1A1. E-mail: [email protected]

This work was supported by the Quebec Network on Suicide, Mood Disorders, and Related Disorders and the Canadian DepressionResearch and Intervention Network (CDRIN).

G.G. has received grants from the Canadian Institute of Health Research (CIHR), the Canada Foundation for Innovation (CFI), the Fondsde recherche du Québec – Santé (FRQS), and the Quebec Network on Suicide, Mood Disorders and Related Disorders. G.G. is an inventor andassignee in patents regarding the sleep properties of selective melatonin MT2 agonists.

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C. Ramelteon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2091. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2092. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2133. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2134. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2135. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

D. Tasimelteon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2131. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2132. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2133. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2134. Results in Healthy Volunteers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2175. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2176. Results in Other Conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2177. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

V. Orexin Receptor Antagonist Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217A. Suvorexant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

1. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2172. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2173. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2174. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2175. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

VI. Antidepressant Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220A. Amitriptyline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220

1. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2202. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2203. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2204. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2205. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2216. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

B. Mirtazapine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2211. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2212. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2213. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2214. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2225. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2226. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

C. Trazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2221. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2222. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2223. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2224. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2225. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2226. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

D. Low-Dose Doxepin (,6 mg/day) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2271. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2272. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2273. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2274. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2275. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2276. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227

ABBREVIATIONS: AUC, area under the curve; BZDs, benzodiazepines; CHMP, Committee for Medicinal Products for Human Use; DSM,Diagnostic and Statistical Manual of Mental Disorders; EEG, electroencephalogram; 5-HT, serotonin; KO, knockout; LC, locus coeruleus; LDT/PPT, lateralpontine tegmentum/pedunculopontine tegmental nuclei; MDD, major depressive disorder; MNPO, median preoptic nucleus;NREM, non-rapid eye movement sleep; OX, orexin; PRM, prolonged-release melatonin; PSQI, Pittsburgh Sleep Quality Index; PTSD,posttraumatic stress disorder; RCT, randomized-controlled trial; REM, rapid eye movement sleep; RT, reticular thalamus; SCN,suprachiasmatic nuclei; SDL, sublaterodorsal nuclei; SSRI, selective serotonin reuptake inhibitor; SWS, slow-wave sleep; vlPO, ventrolateralpreoptic area; WASO, wake after sleep onset; WT, wild type.

198 Atkin et al.

VII. Anticonvulsant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227A. Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227


B. Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2311. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2312. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2313. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2314. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2315. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2316. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231

VIII. Atypical Antipsychotic Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231A. Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233


B. Quetiapine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2351. Mechanism of Action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2352. Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2353. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2354. Results in Insomnia Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2355. Other Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2356. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

IX. Discoveries, Novel Pathways, and Pipelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238A. Discoveries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

1. Adenosine Receptor Agonist. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2382. Casein Kinase-1d/«. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2383. Selective Melatonin MT2 Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2384. Selective Orexin-2 Antagonist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238

B. Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2391. Lumateperone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2392. Piromelatine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239

X. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239Acknowledgments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 240

Abstract——Although the GABAergic benzodiaze-pines (BZDs) and Z-drugs (zolpidem, zopiclone, andzaleplon) are FDA-approved for insomnia disorderswith a strong evidence base, they have many side effects,including cognitive impairment, tolerance, reboundinsomnia upon discontinuation, car accidents/falls,abuse, and dependence liability. Consequently, theclinical use of off-label drugs and novel drugs that donot target the GABAergic system is increasing. Thepurpose of this review is to analyze the neurobiologicaland clinical evidence of pharmacological treatments ofinsomnia, excluding the BZDs and Z-drugs. We analyzedthe melatonergic agonist drugs, agomelatine, prolonged-release melatonin, ramelteon, and tasimelteon; the dualorexin receptor antagonist suvorexant; themodulators of

the a2d subunit of voltage-sensitive calcium channels,gabapentin and pregabalin; the H1 antagonist, low-dosedoxepin; and the histamine and serotonin receptorantagonists, amitriptyline, mirtazapine, trazodone,olanzapine, and quetiapine. The pharmacology andmechanism of action of these treatments and theevidence-base for the use of these drugs in clinicalpractice is outlined alongwith novel pipelines. Thereis evidence to recommend suvorexant and low-dosedoxepin for sleep maintenance insomnia; there isalso sufficient evidence to recommend ramelteon forsleep onset insomnia. Although there is limitedevidence for the use of the quetiapine, trazodone,mirtazapine, amitriptyline, pregabalin, gabapentin,agomelatine, and olanzapine as treatments for

Drugs for Insomnia beyond Benzodiazepines 199

insomnia disorder, these drugs may improve sleepwhile successfully treating comorbid disorders, witha different side effect profile than the BZDs and

Z-drugs. The unique mechanism of action of eachdrug allows for a more personalized and targetedmedical management of insomnia.

I. Introduction

A. Insomnia as a Public Health Burden

Insomnia is a significant public health burden,increasing work absenteeism and health care costsin a large proportion of the population. It causesaltered cognition, emotional disturbances, and re-duced quality of life (Zammit et al., 1999; Wickwireet al., 2016). Insomniacs commonly complain of irri-tability, daytime sleepiness, low energy and motiva-tion, physical discomfort, and impaired cognitivefunctioning (Buysse et al., 2007; Fortier-Brochuet al., 2012; Morin and Jarrin, 2013), not to mentiondeficits in working memory, episodic memory, andsome aspects of executive functioning (Fortier-Brochuet al., 2012).The prevalence rate of insomnia in the general

population has been estimated as low as 5% to as highas 50% (Ohayon, 2002; Morin and Jarrin, 2013). Mostepidemiologic studies have found that about one-thirdof adults (30%–36%) report at least one symptom ofinsomnia, like difficulty initiating sleep or maintainingsleep; this rate drops to 10%–15% when daytimeconsequences, like excessive daytime sleepiness, areadded to the definition (Ohayon, 2002; Morin andJarrin, 2013). From 1999 to 2010, the number ofprescriptions for any sleep medication increased by293% (Ford et al., 2014). Strong increases in thepercentage of office visits resulting in a prescrip-tion for second generation benzodiazepines or Z-drugs(zopiclone, zolpidem, or zaleplon) sleep medications(;350%), benzodiazepine receptor agonists (;430%),and any sleep medication (;200%) were noted (Fordet al., 2014).

B. Changes in the Nosology of Insomnia in Diagnosticand Statistical Manual of Mental Disorders-V

The publication of the fifth edition of the Diagnosticand Statistical Manual of Mental Disorders (DSM-5)(American Psychiatric Association, 2013) fundamen-tally changed the landscape of sleep medicine and thediagnosis of insomnia. In DSM-IV, primary insomniawas distinguished from insomnia that is secondary toanother diagnosis, including major depressive disorderand generalized anxiety disorder. DSM-IV understoodsecondary insomnia as a symptom of a primary psychi-atric disease: the secondary insomnia was expected tonormalize with treatment of the primary disorder(American Psychiatric Association, 2013). However,clinical research has established that this “secondary”insomnia is often resistant to treatment of the primarydisorder: in the STAR*D trial, after remission with a

course of citalopram therapy, 54.9% of remitters con-tinued to experience midnocturnal insomnia and 71.7%continued to experience sleep disturbance in some form(Nierenberg et al., 2010). DSM-5 has eliminated pri-mary insomnia as a diagnosis in favor of insomniadisorder, which may occur alongside other diagnoseslike major depressive disorder. This revised definitionobliges the clinician to treat insomnia as a comorbidity,rather than a symptom of a primary illness. In thisreview, we use the term “insomnia disorder,” exceptwhen a published study explicitly states that it analyzespatients with “primary insomnia.”

C. Clinical Guidelines for Insomnia Treatment andthe Necessity of a Translational Approach

New evidence-based clinical practice guidelines forthe treatment of insomnia disorder were recentlypublished in The Journal of Clinical Sleep Medicine(Sateia et al., 2017a), representing the first comprehen-sive, systematic analysis of single agents for the treat-ment of insomnia disorder, developed using the GRADEmethodology (Grading of Recommendations, Assess-ment, Development, and Evaluation) (Sateia et al.,2017b). Unfortunately, the level of evidence for all ofthe authors’ recommendations was “weak.” This evalu-ation means that the strength of the evidence in thepublished data were low. Notably, all of the recom-mended treatments for sleep onset insomnia besidesramelteon are Z-drugs or BZD hypnotics. For sleepmaintenance insomnia, three of five of the treatmentoptions are Z-drugs or BZDs.

The dearth of strong published evidence led us toadopt a translational approach in exploring treatmentsfor insomnia disorder, integrating the neurobiologicalmechanism of action of each drug gleaned from basicscience and integrating it with reported clinical dataand current medical practice. This approach is cur-rently the standard in pharmacological research and isa priority for federal and foundational grants. Althoughclinical research is critical for establishing evidence-based guidelines for treatment, knowledge gleanedfrom basic research can be helpful for the clinicaljudgment of the therapeutic efficacy of hypnotics andthe treatment of psychiatric comorbidities (Comai et al.,2012a,b).

In this review, we will focus on drugs that are notBZDs or Z-drug, because an extensive literature al-ready exists. Our approach will be translation, offeringalternatives to BZDs and Z-drugs. We will also de-scribe novel hypnotic compounds and pharmaceuticalpipelines.

200 Atkin et al.

D. The Dark Side of Benzodiazepines and Z-Drugsand the Off-Label Use of Other Drugs

Although the market for insomnia medications con-tinues to be dominated by BZDs and Z-drugs, bothcategories of drug have numerous problematic effects asshort-term treatment and, in particular, as long-termtherapy. BZDs are associated with hangover effects thenext day, cognitive or memory impairment, the rapiddevelopment of tolerance, rebound insomnia upon discon-tinuation, car accidents or falls, and a substantial risk ofabuse and dependence (Foy et al., 1995; Hemmelgarnet al., 1997; Soldatos et al., 1999; Ashton, 2005). A largeproportion of people prescribedBZDdrugs become chronicusers. Furthermore, BZDs are a factor in approximately5%–10% of car accidents, although the rate in individualstudies varies from 1% to 65% (Thomas, 1998).Z-drugs also cause cognitive impairments: case con-

trol studies find that BZD or Z-drug use approximatelydoubles the risk of being involved in a motor vehicleaccident (Thomas, 1998; Gunja, 2013b). They can pro-duce dependence (Lugoboni et al., 2014) as well asnext-day cognitive, memory, psychomotor and balanceimpairments (Mets et al., 2011).The problems with BZDs have led clinicians to pre-

scribe other medications that are perceived to be lessharmful or to be less liable to addiction. As an example,in the United States in 2002, the antidepressantmedication trazodone was the most commonly pre-scribed medication for insomnia, with 34% moreprescriptions than the most commonly prescribedFDA-approved treatment (Walsh, 2004). The PrescriberNational Summary Report, Calendar Year 2014 poolsdata from all the Medicare recipients in the UnitedStates. In one cross-sectional study of American adults,3% of 32,328 people used a “prescription medicationcommonly used for insomnia” in the previous month:38% of those who received a hypnotic medication re-ceived Z-drugs, 31% trazodone, 17% BZDs, 11% quetia-pine, and only 5% received doxepin (Bertisch et al.,2014). This study confirms that drugs prescribed off-label are very common in the treatment of insomnia,despite the low number of randomized, controlled trials(RCTs).

II. Sleep Architecture

In mammals, physiological sleep is divided into twostrikingly distinct states known as non-rapid eye move-ment (NREM) and rapid eye movement (REM) sleep.Historically, NREM sleep was subdivided into fourstages (stages 1, 2, 3, 4) defined according to differentelectroencephalogram (EEG) patterns (Rechtschaffenand Kales, 1968). According to the manual of theAmerican Academy of Sleep Medicine published in2007 (Iber et al., 2007), NREM sleep is now dividedinto three progressively deeper stages of sleep named

stage N1, stage N2, and stage N3 (formerly stages 3 and4). REM sleep is now officially referred to as stage R.The EEG pattern in NREM sleep is synchronous andpresents characteristic waveforms: sleep spindles,K-complexes, and high-voltage slow waves. Stage N1accounts for 2%–5% of total sleep time and is the phaseof transition between the awake state and sleep. StageN2 accounts for 45%–55% of total sleep time and occursthroughout the entire sleep period. The descent fromstage N1 to stage N2 is characterized by a decrease inthe frequency of the EEG trace paralleled by an increasein its amplitude. The EEG hallmark of N2 are thetawaves. N2 is also characterized by the occasional occur-rence of a series of high-frequencywaves (8–14Hz) knownas sleep spindles, generated by interactions betweenthalamic and cortical neurons (De Gennaro and Ferrara,2003), and fast and high-amplitude wave forms known asK-complexes also occur (Amzica and Steriade, 2002).According to Rechtschaffen and Kales’ (1968) criteria, aK-complex is defined as anegative slowwave immediatelyfollowed by a positive wave exceeding 0.5 seconds induration.

As stage N2 sleep progresses, high-voltage, slow-wave activity appears as the subject enters stage N3.Stage N3, which corresponds to deep or delta-wavesleep and reflects slow-wave sleep (SWS), occurs mostlyin the first third of the night and accounts for 5%–15% oftotal sleep time. During this sleep stage, there is afurther fall in blood pressure, a slowing of breathing,and a reduction in body temperature, with reducedmuscle activity, although muscles maintain their tonusand thus some movements can be observed.

Stage R or REM sleep is defined by low-amplitudedesynchronized theta EEG activity and represents20%–25% of total sleep time. It occurs in four to fiveepisodes throughout the night and is characterized bycomplete disappearance of muscle tone paradoxicallyassociated with a cortical but also hippocampal activa-tion and rapid eye movements. Since REM sleep EEGactivity closely or paradoxically resembled the EEG ofalert-waking subjects, this sleep stage has been alsoreferred as paradoxical sleep, particularly in studiesconducted in animals.

In physiological conditions, the activity of the brainover the course of the night proceeds from wakingthrough the three stages of NREM sleep and thenREM sleep. NREM sleep and REM sleep continue toalternate through the night in a cyclical fashion, usuallywith a total of four to five sleep cycles throughout thenight. Importantly, as sleep progresses, the time spentin stage N3 becomes shorter, whereas the time spent inREMgets longer. The average length of the first NREM-REM sleep cycle is between 70 and 100 minutes andthat of the second and later cycles is about 90–120 minutes. Sleep architecture, including the durationof the different stages as well as the duration of aNREM-REM cycle, is strongly dependent on the


subject’s age. With aging, humans tend to experience anincrease in the latency to fall asleep, more fragmentedsleep, and less time spent in SWS, particularly in theearly cycles of sleep. One of the parameters providinginformation concerning sleep fragmentation is the“sleep efficiency index” that is a measure of thepercentage of total time in bed actually spent sleepingand is calculated by the sum of the time spent in sleepstage N1, N2, N3, and REM, divided by the total timespent in bed. Specific details on the changes in the sleepstructure occurring during aging are outside the scopeof this paper but are analyzed in a comprehensive recentreview written by Mander et al. (2017). Restorativesleep is not only dependent on an adequate duration ofsleep; the physiological architecture of sleep must beconserved. Under certain conditions and with certainpharmacological treatments, the total duration of sleepmay remain unchanged or increased, but deviationsfrom normal sleep architecture generate increasedsleep fragmentation. Disturbances in subjects’ sleeparchitecture results in a sense of having had nonrestor-ative sleep and is associated with next-day impairmentsin conducting daily activities. Unfortunately, most ofthe drugs currently used as hypnotics—in particularbenzodiazepines, but also Z-compounds to a lesserextent—disturb sleep architecture (Bastien et al.,2003; Gunja, 2013a).

III. The Receptor-Mediated Mechanism of Actionof Hypnotics

Drugs currently used to treat insomnia mainly act onspecific ionotropic or G-protein-coupled receptors lo-cated in specific brain areas. Each receptor modulatesdifferent characteristics of sleep. It is thus important forthe clinician to understand the mechanism of action ofeach hypnotic to target better its effect in individualpatients. This translational approach helps to build amore personalized medicine, targeted to the patient,that overcomes the limitations of overarching clinicalguidelines. While guidelines tend to homogenize thepatient population, a translational approach based onthe mechanism of action of each drug may help totarget the individual patient and his or her particularcomorbidities.

A. GABA Receptor

The most studied receptors in the treatment ofinsomnia are the GABAA receptors, GABA being thechief inhibitory neurotransmitter in the mammaliannervous system,where BZDs and Z-drugs act. BZDs andZ-drugs act as positive allosteric modulators at theGABAA binding site, potentiating GABA’s inhibitoryeffect (Stahl, 2008). The combination of GABA at thereceptor’s agonist site and benzodiazepine-receptoragonists at the allosteric site increases the frequencyof the chloride channel opening to an extent that does

not occur with GABA alone (Stahl, 2008). The result isneuronal inhibition. Similar to other ligand-gated ionchannels, the GABAA receptor is composed of fivesubunits belonging to different subunit classes (a1–6,b1–3, g1–3, d, «, u, p) that are distributed throughoutthe brain differentially; there is also some interindivid-ual variability in their localization. For a detailedreview on this topic, please see Olsen and Sieghart(2009). In this way, BZDs and Z-drugs exert their effectsas sedatives, anxiolytics, anticonvulsants, muscle re-laxants, and hypnotics. The main difference betweenBZDs and Z-drugs is in their receptorial affinitiestoward the different GABAA subunits. BDZs showsimilar affinity to the a1, a2, a3, and a5 receptorsubtypes. In contrast, most of the Z-drugs show higheraffinity for a subset of the alpha subunits, mainly the a1receptor subtype, that seems to be specifically impli-cated in sleep but not in anxiety. Zaleplon, zopiclone,and zolpidem have high affinity and potency for the a1subunit and low affinity and potency at a2 and a3

subunits; eszopiclone—the (S)-enantiomer of zopiclone—has high affinity and potency for the a2 and a3subunits (Nutt and Stahl, 2010). Due to their selectiveagonism, Z-drugsmainly produce sedative and hypnoticproperties and likely display improved tolerability overthe BZDs (Wilson and Nutt, 2007).

This review will focus on alternate mechanisms ofaction that are not directly mediated through GABAreceptors, with the exception of the gabapentinoids(pregabalin and gabapentin). Although pregabalin andgabapentin are analogs of GABA, they do not binddirectly to GABAA or benzodiazepine receptors. Instead,they inhibit the a2d-1 subunit voltage-dependent cal-cium channels. They have been found to increase SWSsleep in patients diagnosed with epilepsy and insomnia(Bazil et al., 2012) and healthy adults (Foldvary-Schaefer et al., 2002; Hindmarch et al., 2005). Furtherdevelopment of novel a2d calcium channels like ataga-balin (PD 200390) was pursued for the treatment ofinsomnia but then discontinued following unsatisfac-tory trial results (Springer Adis Insight, 2017).

B. Serotonin Receptors

The 5-HT-containing neurons of the dorsal raphenuclei discharge maximally during waking and de-crease their firing during SWS; they cease firing duringREM sleep, similar to the norepinephrine-containingneurons of the locus coeruleus (Jones, 2005). The5-HT1A agonist OH-DPAT, which decreases 5-HT firingactivity by activating its autoreceptors (Gobbi et al.,2001) increases REM sleep (Portas et al., 1996). Al-though 5-HT1A receptors are autoreceptors located atthe somatodendritic level, 5-HT1B receptors are autore-ceptors localized at postsynaptic sites. 5-HT1B receptorsare also used as heteroceptors in many cells throughoutthe brain to inhibit the release of neurotransmittersother than serotonin (Marek, 2010). Furthermore,

202 Atkin et al.

serotonergic neurons attenuate cortical activationthrough inhibitory influences on other neurons of theactivating systems, including acetylcholine-containingneurons (Jones, 2005).

C. Serotonin 2 Receptors

The 5-HT2 receptor is located in the prefrontal andorbitofrontal cortex, the (subgenual) anterior cingulatecortex, the occipital, and parietal cortex (vanDyck et al.,2000; Adams et al., 2004; Hinz et al., 2007); in thenucleus accumbens, olfactory tubercule, and the hippo-campus (Pompeiano et al., 1994; Barnes and Sharp,1999; López-Giménez et al., 2001); and in the locuscoeruleus, areas that are important for both sleepmodulation and mood regulation (Szabo and Blier,2001).At the cellular level, 5-HT2A receptors are located on

apical dendrites on pyramidal cells and, particularly insubcortical regions, on local (GABAergic) interneurons(Jakab and Goldman-Rakic, 1998; Barnes and Sharp,1999; Aghajanian and Sanders-Bush, 2002). Althoughthe mechanism of action of 5-HT2A/2C receptor antago-nists has yet to be fully elucidated, it is likely that theypromote SWS via a reduction of inhibitory input to thecells of the ventrolateral preoptic nucleus that fireduring sleep. Through postsynaptic 5-HT2A receptorson GABAergic cells of the reticular thalamus, seroto-nergic fibers from the dorsal raphe and supralemniscalnucleus (B9) modulate the reticular thalamus that inturn regulates sleep and wakefulness (Rodrìguez et al.,2011).Recent studies with more subtype-selective 5-HT2A

and 5-HT2C receptor ligands (antagonists and inverseagonists), as well as experiments in knockout (KO)mice,support a role for 5-HT2A receptor subtypes in pro-moting SWS and the 5-HT2C receptor in promotingREM (Popa et al., 2005).Ritanserin, a potent antagonist of the serotonin

receptors 5-HT2A and 5-HT2C, has been found to in-crease SWS in healthy volunteers to a greater degreethan ketanserin (a drug with less potent effects as anantagonist of the 5-HT2C receptor, used clinically as anantihypertensive) (Sharpley et al., 1994). Ritanserinwas never commercialized for safety problems, althoughit did show efficacy at increasing SWS and delta activityin young male poor sleepers (Viola et al., 2002), under-lining the importance of these receptors in the regula-tion of SWS.Interestingly, many hypnotic drugs prescribed off-

label (trazodone, mirtazapine, olanzapine, quetiapine)act through 5-HT2A and 5-HT2C receptors to enhancesleep (Landolt and Wehrle, 2009). Trazodone, the first5-HT2A antagonist, was initially developed as an anti-depressant, but is currently one of the most commonhypnotics prescribed in the clinic (Bertisch et al., 2014).Similarly, the 5- and 10-mg doses of olanzapine com-pared with placebo, significantly increased SWS, sleep

continuity measures, and subjective sleep quality(Sharpley et al., 2000). See Tables 1 and 2 for thereceptorial affinities of each drug and for their effects onsleep architecture, respectively.

D. Serotonin 1A Receptors

The 5-HT1A receptor is the main 5-HT autoreceptor,located at the somatodendritic level of the 5-HT neuronsof the dorsal raphe as well as at synaptic terminals inthe hippocampus and prefrontal cortex. 5-HT1 knockout(KO) mice have increased 5-HT firing activity (Richeret al., 2002) and decreased REM sleep, but not SWS(Boutrel et al., 2002); the 5-HT1A agonist OH-DPATinduces a decrease in REM sleep in the first 2 hoursafter injection followed by an increase in REM after 6–8hours (Boutrel et al., 2002). 8-OH-DPAT (1.0–4.0 mg)injected into the dorsal raphe nucleus increased slow-wave sleep and decreased wakefulness, although itsadministration of subcutaneously induced biphasiceffects such that low doses decreased wakefulness andincreased slow-wave sleep while higher doses inducedopposite effects, perhaps due to the opposing effects ofthe 5-HT1A autoreceptors and heteroreceptors (Montiand Jantos, 1992). Given these opposing and complexeffects, employing 5-HT1A partial agonists is a rationalapproach to insomnia, given their capacity to act asagonists when the levels of endogenous agonist are lowand as antagonists when the levels of endogenousagonist are high.

5-HT1B knockout mice have increased REM sleep andlower SWS during the light phase and lack REM sleeprebound after deprivation, suggesting that the blockageof 5-HT1B receptors increases REM and decreasesNREM sleep (Boutrel et al., 1999). In agreement withthis finding, in wild-type (WT) mice, the 5-HT1B ago-nists CP 94253 andRU24969 induced a dose-dependentreduction of paradoxical sleep during the 2–6 hoursafter injection, whereas the 5-HT1B/1D antagonist GR127935 enhanced paradoxical sleep (Boutrel et al.,1999).

Quetiapine and trazodone both act on 5-HT1A recep-tors as partial agonists (Richelson and Souder, 2000;Odagaki et al., 2005).

E. Noradrenaline Receptors

Similarly to 5-HT neurons, the norepinephrine-containing neurons of the locus coeruleus (LC) nucleidischarge maximally during waking and decreasetheir firing during SWS; they are nearly silent duringparadoxical or REM sleep (Jones, 2005).

The most important adrenergic receptors implicated insleep are a1 and a2 receptors. a2 Receptors are located atpresynaptic terminals, acting as themain norepinephrineneuron autoreceptors, although they are also present atthe postsynaptic terminal. The activation of the a2

autoreceptor decreases LC activity, while, in contrast, a2

receptor blockade using a2 antagonists increases the


firing activity of LC neurons (Gobbi and Blier, 2005). Infact, although the a2 agonist clonidine decreases LCactivity and thus promotes sleep (particularly SWS) whileinhibiting REM (De Sarro et al., 1987; Berridge et al.,2012), there is evidence that the selective a2 antagonistyohimbine increases wakefulness, at least in rats (Mäkeläand Hilakivi, 1986).

However, selective knockdown of a2A-adrenergicreceptors in the LC abolished a2 agonist dexmedetomidine-induced loss-of-righting-reflex, but not sedation (Zhanget al., 2015). These findings implicate other structuresbesides the LC in a2 receptorial regulation of arousal:these structures include the preoptic area, in which a2

receptors are situated on GABAergic interneurons,which influence sleep through reciprocal inhibitoryprojections to the W systems; or the prefrontal cortex,where a2 receptors are likewise situated on GABAer-gic neurons (Manns et al., 2003; Luppi et al., 2017).

Indeed, when GABAergic neurons (“OFF neurons”)containing a2 receptors located in the prefrontal cortexare stimulated during SWS, their firing activity ceases,which likely produces paradoxical or REM sleep (Mannset al., 2003). This complex a2 receptor-mediated mech-anism may account for the manner in which the a2

antagonist mirtazapine promotes sleep, although itincreases LC firing (Gobbi and Blier, 2005).

The a1 and beta adrenergic receptors are also in-volved in the regulation of arousal. While individualadministration of the a1 blocker prazosin producesdecreased behavioral arousal and individual adminis-tration of the beta noradrenergic antagonist timololhas no effect, coadministration of prazosin and timololproduces a substantial, synergistic increase in slow-wave firing activity with a corresponding strongsedative effect behaviorally (Berridge and Espana,2000).

F. Dopamine Receptors

Dopamine neurons are also active during wakeful-ness and decrease during REM sleep and SWS (Montiand Monti, 2007). In particular, the dopamine D2

receptor is one of the main receptors involved in sleepregulation. D2KO mice exhibit a significant decrease inwakefulness, with a concomitant increase in NREMandREM sleep and a drastic decrease in low-frequencyelectroencephalogram delta power (0.75–2 Hz) ofNREM sleep, especially during the first 4 hours follow-ing lights off. In agreement with these findings, the D2

antagonist raclopride mimicked these effects in WTmice (Qu et al., 2010). Similarly, the dopamine D2

receptor antagonists haloperidol and chlorpromazinehave the tendency to induce sleepiness in humansubjects, while blockers of the dopamine transporterlike amphetamine and modafinil increase wakefulnessby increasing extracellular levels of dopamine in thesynapse (Schmitt and Reith, 2010). In contrast, para-doxically, the antiparkinsonian D2 agonist ropinirole

TABLE

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etiapine.

204 Atkin et al.

also induces sleepiness, but mostly daytime sleepinessand sleep attacks during the day (Paus et al., 2003),likely through activation of D2 autoreceptors that de-crease DA firing activity during the daytime.

G. Orexin Receptors

The orexins (OXs), also known as the hypocretins, area pair of excitatory neuropeptide hormones with ap-proximately 50% sequence homology: orexin-A andorexin-B (hypocretin-1 and -2). They are producedexclusively by a population of neurons in the lateralhypothalamic area (de Lecea et al., 1998; Sakurai et al.,1998). Physiological effects of the OXs in the brainresult from the activation of two G-protein-coupledreceptors, named orexin 1 (OX1) and orexin 2 (OX2)receptors (Sakurai et al., 1998). OX1 has one-orderhigher affinity for OX-A than for OX-B, whereas OX2

binds OX-A and OX-B with similar affinities.The orexinergic system is known to promote behav-

ioral arousal, increase food intake and locomotor activ-ity (Sakurai et al., 1998; Nakamura et al., 2000), andinduce wakefulness (Hagan et al., 1999). In addition,the OXs appear to regulate the stress response byincreasing the activity of the hypothalamic-pituitaryaxis (Al-Barazanji et al., 2001). Furthermore, they areimplicated in the pathophysiology and treatment ofdepressive-like behavior (Nollet et al., 2011).KO animals that lack the prepro-orexin gene, OX2

gene, or orexin neurons have narcolepsy-like behavior,including fragmentation of sleep/wakefulness, directtransitions from wake to REM sleep, and sudden lossof muscle tone while still awake (cataplexy) (Chemelliet al., 1999; Lin et al., 1999; Hara et al., 2001; Willieet al., 2003). However, OX1KOmice havemild or almostno abnormality in the regulation of sleep and wakeful-ness, suggesting that the orexin signal through OX2 hasa more critical role in the regulation of sleep andwakefulness, especially in the maintenance of arousal.

The expression pattern of orexin receptors matches theafferent projections of orexin neurons throughout thebrain. The few studies using selective antagonists ofthe OX1 and OX2 receptors have demonstrated thatselective blockade of OX2, but not OX1, increases REMand NREM. However, coadministration of the selectiveOX1 antagonist and the selective OX2 antagonist in-tensified the effect of OX2 blockade on REM and NREM(Dugovic et al., 2009). Other studies have agreed thatOX1 may play a role in the regulation of sleep andarousal (Mieda et al., 2011).

A novel orexin antagonist (suvorexant) was recentlyput on the market and other selective orexin antago-nists are under development (Winrow and Renger,2014).

H. Melatonin Receptors

The neurohormonemelatonin activates twoG-protein-coupled receptors, MT1 and MT2. Melatonin is impli-cated in circadian rhythms and sleep regulation,but the differential role of its individual receptorsremains undefined.

Melatonin receptors have a specific localization thatimplicates them in physiological functions related tosleep (Lacoste et al., 2015). MT2 receptors are located inthe reticular thalamus, an area involved in modulatingSWS (Steriade et al., 1993), as well as the substantianigra (pars reticulata), supraoptic nucleus, red nucleus,and the CA2, CA3, CA4 areas of the hippocampus andSCN (Ekmekcioglu, 2006; Ochoa-Sanchez et al., 2011),while MT1 is located in the locus coeruleus, the dorsalraphe, and areas CA2 and CA3 of the hippocampus andSCN (Lacoste et al., 2015).

Recently our group has better characterized thedifferential role of each receptor in sleep function usingMT1KO, MT2KO, and double MT1-MT2KO as well asselective MT2 ligands (Comai et al., 2013). MT2KOmicehave a selective disruption of SWS during the inactive

TABLE 2Summary of the effects of the different hypnotic drugs on the sleep architecture and their potential to induce dependence liability

Drug Latency toSleep Onset

Effect on NREM Sleep Effect onREM Sleep

SleepEfficiency

DependenceLiabilityStage N1 Stage N2 Stage N3 also referred as SWS

Benzodiazepines ↓ ↓ ↑ ↓ ↓ ↑ HighZ-drugs ↓ ↔ ↑ ↔ ↔ ↑ ModerateRamelteon ↓ ↔ ↑ ↓ ↔ ↑ LowTasimelteon ↓ n.a. n.a. n.a. ↑ ↑ LowMelatonin prolonged-release ↓ ↔ ↔ ↔ ↔ ↑ LowAgomelatine ↓ ↔ ↔ ↑ ↔ ↑ LowLow-dose doxepin ↓ ↔ ↑ ↔ ↔ ↑ LowSuvorexant ↓ ↔ ↑ ↔ ↑ ↑ LowTrazodone ↔ ↔/↓ ↔/↓ ↔/↑ ↔/↓ ↔ LowAmitryptiline ↓ n.a. n.a ↑ ↓ ↑ LowQuetiapine ↓ ↔ ↑ ↔↓ ↓ ↑ LowOlanzapine ↓ ↔ ↔/↑ ↑ ↓/↔/↑ ↑ LowGabapentin ↔ ↔ ↔ ↑ ↔ ↑/↔ ModeratePregabalin ↓ ↔ ↔ ↑ ↓ ↑ ModerateMirtazapine ↔ ↓ ↔ ↑ ↔ ↑ Low

↑: Increase; ↓: decrease; ↔: no change. n.a.: not assessed.


phase and increased wakefulness, whereas MT1KOmice have a selective disruption of REM during theinactive phase and an increase of NREM. These resultselucidate the opposing and differential effects of the tworeceptors in the neurobiology of sleep.DualMT1-MT2 KOmice only show a small increase in

wakefulness, without a difference in total sleep com-pared with their WT counterparts (Comai et al., 2013),establishing that the MT1 and MT2 receptors may haveopposing roles. This interpretation fits with the factthat melatonin and drugs that bind both MT1 and MT2

only modify the time to induction of sleep, without aglobal effect on total sleep time or sleep architecture(Comai et al., 2015). Thus, the absolute benefit ofmelatonin compared with placebo is smaller than otherpharmacological treatments for insomnia (Ferracioli-Oda et al., 2013). Similarly, ramelteon, a dual agonist ofboth MT1 and MT2, has only been approved by the FDAfor the treatment of insomnia characterized by difficultywith sleep onset; it does not affect total sleep duration orincrease SWS.

I. Histamine Receptors

The sole source of brain histamine is neurons local-ized in the hypothalamic tuberomammillary nuclei(Haas and Panula, 2003). These neurons project axonsto the whole brain, although functionally distincthistaminergic neural circuits differentially influenceindividual brain regions. Four histamine receptors havebeen identified: H1, H2, H3, and H4 (Takahashi et al.,2002). In general, histamine modulates inflammatoryresponses through peripheral H1 receptors and modu-lates gastric acid secretion through peripheral H2

receptors. This led to the discovery and therapeuticuse of potent selective H1 and H2 receptor antagonists.In contrast to the H1, H2, and H4 receptors, the H3

receptor is predominantly expressed in the CNS(Lovenberg et al., 1999; Oda et al., 2000), acting as anautoreceptor on presynaptic neurons and controllinghistamine turnover. H3 receptors have also been shownto act as heteroreceptors in dopamine-, serotonin-,noradrenaline-, GABA-, and acetylcholine-containingneurons (Schlicker et al., 1994).The H1 receptor is probably the most important

physiological histamine target in the maintenance ofwaking. In animal studies, H1 receptor agonists increasewake duration (Passani and Blandina, 2011). H1 receptorKO mice show fewer incidents of brief awakening (,16-second periods), prolonged durations of NREM sleepepisodes, a decreased number of state transitions betweenNREM sleep and wakefulness, and a shorter latency forinitiating NREM sleep. When the H3 receptor antagonistciproxifan was administered intraperitoneally to WTmice, wakefulness increased in the mice in a dose-dependent manner but did not increase at all in H1KOmice, highlighting the interdependent functional relation-ship between H1 and H3 receptors (Huang et al., 2006).

H3KO mice show clear signs of enhanced histamin-ergic neurotransmission and vigilance, with higherEEG u power during spontaneous wakefulness andduring behavioral tasks. During the dark period, theydisplay deficient wakefulness and signs of sleep de-terioration, such as pronounced sleep fragmentationand reduced cortical slow activity during SWS, whichoccurs due to a desensitization of postsynaptic hista-minergic receptors as a result of constant histaminerelease (Gondard et al., 2013).

Prescription drugs like mirtazapine, quetiapine, andhydroxyzine—not tomention nonprescription sleep aidslike diphenhydramine—act on histaminergic neurons.

J. Other Receptors

Other receptors involved in sleep, but which remainto be pharmacologically exploited, include the adeno-sine A1 and A2 receptors (Jacobson and Gao, 2006).Interestingly, the arousal effect of the adenosine antag-onist caffeine is mediated through the adenosine A2A

receptor, but not the A1 receptor (Huang et al., 2005).Adenosine mediates the somnogenic effects of prior

wakefulness and likewise plays an important role in theregulation of the duration and depth of sleep afterwakefulness (reviewed by Greene et al. (2017). Phar-macological data suggest that A1A receptors are in-volved in the regulation of sleep, although a lack of A1A

receptors is not sufficient to prevent homeostatic regu-lation of sleep (Stenberg et al., 2003). It is conceivablethat although the A1A receptor is an important factor forsleep regulation in normal animals, other factors, suchas the A2A receptor, may compensate for the absence ofthe A1A receptor when it is deleted in knockout models.Indeed, it has been shown that the A2A receptor has akey role in adenosine-mediated sleep-promoting effects(Urade et al., 2003).

Melanin-concentrating hormone (MCH) neurons areknown to be active during REM sleep and the stimula-tion of these neurons promotes REM sleep; indeed,electrophysiological recordings of MCH neurons acrossthe natural sleep-wake demonstrates that they do notfire during waking, fire occasionally during NREMsleep, and fire maximally during REM sleep (Hassaniet al., 2009). Importantly, they are colocalized withorexin neurons in the lateral hypothalamic area andadjacent zona incerta but as unique cell populationsspatially intermingled with each other (reviewed byYamashita and Yamanaka (2017).

Importantly, when MCH neurons are active, theyinhibit orexin neurons, and knockout of MCH peptideand the MCHR1 receptor in mice produces less REMand NREM sleep. Optogenetic studies have confirmedthe role of MCH neurons in inducing REM sleep:optogenetic activation of these cells during NREM sleepproduces REM, but activation during wakefulnessproduces no effect. MCH neurons also play a role inNREM sleep, because temporally controlled ablation of

206 Atkin et al.

these cells increases wakefulness and decreases NREMsleep duration without affecting REM sleep (Tsunematsuet al., 2014).

K. From Receptors to Sleep Circuits.

The manner in which unique neurotransmitters andindividual brain areas reciprocally interact is still notunderstood in its entirety. The neural circuits thatgenerate arousal and sleep (both NREM and REM)remain to be completely elucidated.Humans are diurnal mammals, with a circadian clock

that promotes wakefulness during the day, even ashomeostatic sleep drive builds up. Importantly, sleeptiming is phase-linked to intrinsic circadian rhythm-controlled temperature rhythms as well as extrinsiclight and dark signaling (Scammell et al., 2017).In mammals, the circadian rhythm is organized by

the suprachiasmatic nuclei (SCN). The retinohypotha-lamic tract, which contains the intrinsically photosen-sitive retinal ganglion cells and the photopigmentmelanopsin, projects directly and monosynaptically tothe SCN via the optic nerve and the optic chiasm. TheSCN, which is rich in MT1 and MT2 receptors (Lacosteet al., 2015), projects to the paraventricular nucleus,and the “darkness” signal is eventually relayed tosympathetic fibers that innervate the pineal gland,which produces melatonin in response to darkness.Melatonin then stimulates the brain’s MT2 receptorsin the NREM sleep activating regions of the brain: thereticular thalamus and the preoptic areas, includingboth the ventrolateral preoptic area (vlPO) and themedian preoptic nucleus (MNPO) (Ochoa-Sanchezet al., 2011; Lacoste et al., 2015). Specifically, theMNPO appears to regulate the firing activity of thevlPO (Chou et al., 2002). It has been shown that duringthe transition from wakefulness to sleep, the MNPO—

which specifically contains neurons that fire duringslow-wave and paradoxical sleep, with slow dischargingactivity,5 Hz—begin to fire not before, but after, sleeponset, with a gradual increase in discharge rate (Sakai,2011). During NREM sleep, the vlPO sends inputs thatact to reduce the activity of the orexinergic arousalsystem and the monoamine nuclei (including the ven-tral tegmental area containing DA neurons, the dorsalraphe containing 5-HT neurons, and the LC containingNE neurons) by releasing the inhibitory neurotrans-mitters GABA and galanin. As a feedback mecha-nism, vlPO neurons receive reciprocal inputs from thearousal nuclei, including the ventral tegmental area,dorsal raphe, and LC; the vlPO also receives input fromthe histaminergic tuberomammillary nucleus(Adamantidis et al., 2010).The reticular thalamus (RT) is another area essential

for NREM sleep: people suffering from fatal familialinsomnia show thalamic disruption that inactivatestheir ability to sleep, which is paralleled by a dysfunc-tion in melatonin production (Portaluppi et al., 1994).

RT neurons discharge in burst activity exclusivelyduring NREM, and thalamocortical pathways projectthis synchronous burst activity, intermingled withperiods of silence, onto the cortex. This rhythmic firingactivity generates the synchronized EEG pattern typi-cal of SWS, which produces disconnection between thecortex and the outside world (Steriade and Timofeev,2003). The RT is also rich in melatonin MT2 receptors,which are likely activated at the beginning of sleep(Ochoa-Sanchez et al., 2011). Disconnection betweenthe prefrontal cortex and sensory input is greatestduring Stage 4 of NREM sleep, when the frequency ofthe EEG trace is the lowest and its amplitude is thehighest. Conversely, during wakefulness, the RT andthalamocortical neurons are depolarized by inputs fromthe reticular activating system of the brain stem anddischarge instead with a tonic activity (adapted fromSteriade et al., 1993; Purves et al., 2004).

REM sleep, in contrast, is regulated by other brainareas. Many researchers have hypothesized that REMsleep ismediatedmostly through cholinergic neurons locatedin the lateralpontine tegmentum/peduncolopontine teg-mental nuclei (LDT/PPT). These neurons are activeduring REM sleep and generate the cortical activationand atonia typical of this sleep stage and are inactiveduring NREM sleep. Indeed, LDT/PPT neurons sendinputs to the ventromedial medulla, which inhibitsmotor neurons by releasing GABA and glycine into thespinal and brain stemmotor neurons, producing atonia.LDT/PPT neurons are also the main source of acetyl-choline to the thalamus: activation of this acetylcholinepathway depolarizes thalamic neurons, generating thecortical activation associated with REM sleep anddreaming. Other nuclei important for REM sleep regu-lation are 1) the sublaterodorsal nucleus (SDL), whichproduces GABA and glutamate and projects to theglycinergic/GABAergic premotor neurons in the ventro-medial medulla and ventral horn of the spinal cord, andthrough these circuits likely inhibits motor neuronsduring REM sleep, and 2) the MCH-containing neuronsthat fire during REM sleep and decrease their activityduring NREM sleep and wakefulness. The “REM-offversus REM-on” theory of REM sleep hypothesizes thatduring the REM-on period, LDT/PPT, SDL, and MCHneurons are active and inhibit monoamine neurons aswell asmotor neurons, while during the REM-off period,the vlPAG/LPT is inhibited by MCH neurons and otherneurotransmitters (Saper et al., 2001; reviewed inEspaña and Scammell, 2011).

Other cholinergic nuclei that are active during REMsleep and wakefulness include the basal forebrain andthe lateral hypothalamus; these same nuclei areinhibited during NREM sleep.

The manner in which the brain alternates cycles ofNREM and REM remains unknown, although someresearchers have proposed the existence of a mutuallyinhibitory circuit between vlPAG/LPT and the SDL.


Figure 1 is a schematic representation of nuclei impor-tant during sleep, illustrating the circuits that modu-late the sleep/wake cycle and their respective receptors.

IV. Melatonergic Drugs

A. Agomelatine

1. Mechanism of Action. Similar to melatonin,agomelatine inhibits firing activity in the SCN, likelythrough its full agonist activity at MT1; it is also anagonist at the MT2 receptor (McAllister-Williams et al.,2010). Agomelatine has low affinity for the 5-HT1A and5-HT2B receptors, and its effects are thought to bemediated by its antagonism of the 5-HT2C receptor,with a pKi of 6.2 at human receptors (Millan et al.,2003). In animals, chronic administration of agomela-tine produces a dose-dependent increase in dopamineand norepinephrine levels in the frontal cortex, withoutan effect on serotonin (European Medicines Agency,

2008a); like many other antidepressants, agomelatineadministration is associated with increased expressionof brain-derived neurotrophic factormRNA and enhancedneurogenesis in the hippocampus (Banasr et al., 2006). Inone study, agomelatine given at the onset of the late phaseinduced no changes in rat polygraphic recordings. How-ever, when it was administered shortly before dark phase,agomelatine (10 and 40 mg/kg) enhanced the duration ofREM and SWS sleep and decreased the duration of thewake state for 3hours (Descamps et al., 2009). A summaryof the pharmacological targets of agomelatine is reportedin Table 1.

2. Pharmacokinetics. Agomelatine is rapidly andwell-absorbed following oral administration (.80%)(EuropeanMedicines Agency, 2016). However, absolutebioavailability is low and variation between individualsis substantial, with increased bioavailability in womencompared with men. Elderly people likewise experiencegreater exposure to the drug, with AUC and Cmax 4- and

Fig. 1. Brain areas involved in the regulation of sleep and wakefulness with their respective receptors. Top left, green: When the brain enters NREM,neurons of the arousal system decrease their firing activity. This includes the serotonin neurons of the dorsal raphe (DR), the dopaminergic neurons ofthe ventral tegmental area (VTA), and the noradrenergic neurons of the locus coeruleus (LC). These neurons are silent during REM. OX1- and OX2-containing orexinergic neurons of the lateral hypothalamus decrease their firing activity during NREM and REM. The histaminergic H1-containingneurons of the tuberomammillary nucleus (TMN) decrease their firing activity during sleep. During wakefulness, these arousal centers each sendwidespread ascending projections to the cerebral cortex, stimulating cortical desynchronization with high-frequency gamma and low-frequency thetarhythmic activity. Bottom left, black: The receptors likely responsible for the switch from wakefulness to NREM sleep are MT1 and MT2 receptorsexpressed in suprachiasmatic neurons, which receive inputs directly from the retinohypothalamic tract (RHT), influenced by light and external stimuli.The transition from NREM and REM is controlled by the ventrolateral periaqueductal gray area (vlPAG), containing melatonin MT2 receptors, GABA,and glutamate receptors. Top right, red: During NREM sleep, two nuclei are particularly active: the reticular thalamus (RT), containing melatonin MT2and GABA receptors, which is responsible for thalamocortical input to the prefrontal cortex (showing synchronized activity during NREM), and theventrolateral preoptic area (vlPAG), containing GABA and galanin receptors, which inhibits noradrenergic, serotonergic, cholinergic, histaminergic,and hypocretinergic neurons. These nuclei play a role in the “reciprocal inhibitory” model of the sleep-wake switch. Bottom right, blue: The vlPAG is aputative “REM ON” nucleus, switching the brain to the REM sleep mode. During REM, the sublateral nucleus (SLD), the basal forebrain (BF), and thelateral tegmentum/ pedunculopontine tegmentum (LDT/PPT, rich in acetylcholine receptors) and the ventromedial medulla (VM) neurons becomeparticularly active. Note that the basal forebrain is active in REM and wakefulness and inhibited during NREM.

208 Atkin et al.

13-fold higher for patients $75 years old compared withpatients ,75 years old (European Medicines Agency,2016). Smoking, oral contraceptive pills, and the presenceof hepatic impairment likewise significantly affect ago-melatine’s pharmacokinetics. The metabolism of agome-latine occurs mainly via hepatic CYP1A2, and CYP1A2polymorphisms have been shown to significantly affectthe pharmacokinetics the drug (Song et al., 2014).3. Indications. Agomelatine is approved for use in

the European Union and Canada for the treatment ofmajor depressive disorder (MDD) but not approved inthe United States (Sansone and Sansone, 2011). Clin-ical studies examining the hypnotic effects of agomela-tine are detailed in Table 3.4. Results in Insomnia Disorder. No studies of ago-

melatine as a treatment of insomnia disorder were found.5. Other Results. The studies of agomelatine were

conducted in people diagnosed with major depressivedisorder. In a 6-week randomized, double-blinded com-parison study (N = 332) in people diagnosed with majordepressive disorder (Kasper et al., 2010), agomelatinewas significantly superior to sertraline at improvingsleep latency (P , 0.001) and sleep efficiency (P ,0.001); furthermore, symptoms of depression (P, 0.05)and anxiety (P, 0.05) improved significantlymore withagomelatine than with sertraline. Another randomized,double-blinded study comparing agomelatine and esci-talopram (N = 138) found that agomelatine resulted in agreater reduction in sleep latency than escitalopram fromweek 2 onward (Quera-Salva et al., 2011). Moreover,although escitalopram reduced the number of sleep cyclesrelative to baseline, agomelatine preserved the number ofsleep cycles. Finally, a review that pooled the results fromthree randomized studies (N=721) comparingagomelatineto SSRIs or venlafaxine (Quera-Salva et al., 2010) estab-lished that agomelatine increases SWS, improves sleepefficiency, and resynchronizesSWSto the first sleep cycle ofthe night in patients with major depressive disorder whilenot changing the amount or latency of REM sleep.6. Conclusion. A summary of the effects of agomelatine

on sleep architecture is presented in Table 2. There is goodevidence that agomelatine is superior to other antidepres-sants at reducing sleep latency in patients with majordepressive disorder based on one review and two random-ized, double-blind comparison studies (Kasper et al., 2010;Quera-Salva et al., 2010, 2011).Based on these samestudies,the evidence is weak for the use of agomelatine in insomnia.

B. Prolonged-Release Melatonin

1. Indications. Melatonin is FDA-approved as adietary supplement with no dosage restriction. InEurope, prolonged-release melatonin 2 mg/day is ap-proved for the treatment of insomnia in elderly patients.PRM is a new option in the treatment arsenal for

insomnia. It is targeted specifically toward older adults,potentially because endogenous melatonin productiondeclineswith age and PRMmimics the pharmacokinetics

of endogenous melatonin (Lemoine and Zisapel, 2012).However, a 3-week RCT found that the effects of PRM inpatients with low endogenous melatonin among all agesdid not differ fromplacebo (Wade et al., 2010); in contrast,PRM significantly reduced sleep latency compared withthe placebo in elderly patients irrespective of melatoninlevels (219.1 vs.21.7minutes). This finding supports theidea that PRM has targeted efficacy specifically amongthe elderly, the same group of patients for whombenzodiazepine treatment is discouraged due to theincreased risk of falls, accidents, and cognitive impair-ment (“What’s Wrong,” 2004). Clinical studies examiningthe hypnotic effects of PRM are detailed in Table 4.

2. Pharmacokinetics. Absorption of orally ingestedmelatonin is complete in healthy adults, although itmay be decreased by up to 50% in the elderly (EuropeanMedicines Agency, 2017). Melatonin has linear phar-macokinetics over the dosage range of 2–8 mg, althoughbioavailability is only about 15%, and the rate ofprolonged-release melatonin absorption is affected byfood: the presence of food delayed the absorption ofprolonged-release melatonin, resulting in a later andlower peak plasma concentration in the fed state. Themetabolism of melatonin is mainly mediated by CYP1Aenzymes, although exogenous administration of melato-nin does not induce these enzymes, even at suprather-apeutic dosages (European Medicines Agency, 2017).

3. Results in Insomnia Disorder. Four RCTs andone open-label trial found PRM effective in the treat-ment of primary insomnia in the elderly. Only one RCT,the largest one (N = 791), included patients below55 years of age; this study demonstrated that PRMwas only effective in the subgroup of patients over55 years old, validating its specific efficacy among theelderly but not other groups (Wade et al., 2010). Amongthe elderly in this study, PRM reduced subjective sleeplatency compared with baseline by 219.1 versus 21.7 minutes for placebo.

4. Other Results. One RCT (N = 80) in patients withmild to moderate Alzheimer’s disease with and withoutinsomnia comorbidity found that patients treated withPRM had significantly superior cognitive performanceduring the trial; in contrast, PSQI scores did notsignificantly change in the study, although sleep effi-ciency was found significantly to improve in patientswith and without comorbid insomnia (Wade et al., 2014).

5. Conclusion. A summary of the effects of PRM onsleep architecture is presented in Table 2. There is goodevidence that PRM is effective in the treatment ofinsomnia disorder in adults over 55 years of age, basedon four RCTs. There is also evidence that PRM is noteffective in the treatment of primary insomnia inyounger adults, based on one RCT (Wade et al., 2010).

C. Ramelteon

1. Mechanism of Action. Ramelteon is a potent andhighly selective agonist at the MT1 and MT2 receptors


TABLE

3Sum

maryof

stud

iesas

sessingtheeffectsof

agom

elatine(A

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sleep

Study

Age

Diagn

osis

Design+Numbe

rof

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nts

Results

Adv

erse

Eve

nts

Con

clusion

Kas

peret

al.(201

0)18

–60

Major

depr

essive

disord

er6-wkrand

omized

,do

uble-blind

compa

risonstud

yof

AGM

25-50mg/da

yvs.sertraline

50–10

0mg/da

y.N

=33

2.

AGM

was

sign

ifican

tlysu

perior

tosertraline

from

week1to

week

6by

impr

ovem

entin

SOL,

P,

0.00

1,an

dim

prov

emen

tin

SE,P

,0.00

1.Dep

ressivean

dan

xietysymptom

salso

impr

oved

morewithAGM

than

sertraline

.

Incide

nceof

trea

tmen

t-em

erge

ncyad

verseev

ents

(AEs)

was

48.0%

forAGM

and49

.1%

forsertraline

.Mostcommon

repo

rted

AEs

inboth

grou

pswerehe

adache

,drymou

th,a

nddiarrhea.

Fatigue

morecommon

inAGM

grou

pan

dhy

perhyd

rosismore

common

insertralin

egrou

p.

AGM

iseffectiveat

redu

cing

symptom

sof

insomniain

depr

essed

patien

tsan

dsign

ifican

tly

supe

rior

tosertraline

.

Que

ra-Salva

etal.(20

10)

NS

Major

depr

essive

disord

erRev

iew

withpo

oled

analysis

ofthreerand

omized

stud

iesat

end-po

intor

after6or

8wk

oftrea

tmen

twithAGM

25/50mg/da

yvs.SSRIs

orve

nlafax

ine.

N=72

1.

HAM-D

Item

4,ea

rlyinsomnia:

AGM

25/50mg/da

yredu

ced

scorefrom

1.46

0.7to

0.56

0.7

aten

dpoint

vs.placeb

oredu

ced

scorefrom

1.46

0.7to

0.76

0.8,

P,

0.00

1.For

HAM-D

Item

4,middleinsomnia:

compa

rison

betw

eenplaceb

oan

dAGM

yielde

dP

=0.01

5.For

HAM-D

Item

5,late

insomnia:

compa

risonbe

tweenplaceb

oan

dAGM

yielde

dP

=0.00

6.

Not

analyz

ed.

AGM

iseffectiveat

redu

cing

symptom

sof

insomniain

depr

essed

patien

tsan

dsu

perior

toothe

ran

tide

pressa

nts.

Que

ra-Salva

etal.(20

11)

19–60

Major

depr

essive

disord

er6-wkwithop

tion

al18

-wk

extens

ionpe

riod

rando

mized

,do

uble-blind

compa

risonstud

yof

AGM

25–50

mg/da

yvs.escitalop

ram

10–20

mg/da

y.N

=13

8.

AGM

sign

ifican

tlyredu

cedSOL

from

week2on

wards

compa

red

withescitalopr

am:estimated

differen

ce(m

inute)

atweek

2was

219

[ 230

,29],P

,0.00

1;at

week6was

214

[224

,25],

P=0.01

3;at

wee

k24

was

218

[233

,23],P

,0.00

01.T

STwas

increa

sedwithAGM

but

decrea

sedwithescitalopr

amrelative

toba

seline

.SE

was

stab

lewithAGM

butde

crea

sed

withescitalopr

am.Num

berof

sleepcycles

was

stab

lewith

AGM

butde

crea

sedwith

escitalopr

am.

Withd

rawalsdu

eto

AEswere

less

freque

ntwithag

omelatine

(3%)than

escitalopram

(8%).

Proportionof

patie

ntsreporting

atleaston

eAE

was

lower

with

agom

elatinethan

escitalopram

(66%

vs.8

2%,P

=0.03

8).

Hea

dache,

nasoph

aryn

gitis,

andna

usea

werethemost

common

AEsin

both

grou

ps.

AGM

iseffectiveat

redu

cing

symptom

sof

insomniain

depr

essed

patien

tsan

dsu

perior

toescitalopr

am.

210 Atkin et al.

TABLE

4Sum

maryof

studies

assessingtheeffectsof

thepr

olon

ged-releas

emelaton

inform

ulation(PRM)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Arbon

etal.(201

5)55

–64

Hea

lthypa

rticipan

tsDou

ble-blind,

placeb

o-controlle

d,four-w

aycrossovertrial.PRM

2mgvs.tem

azep

am20

mgvs.

zolpidem

(10mg)

vs.p

lacebo

.N

=16

PRM

hasminor

effectson

stag

eN3in

compa

risonwiththose

oftemaz

epam

andzolpidem

.

10ad

verseev

ents

ofmild

intensity

dueto

PRM.The

mostcommon

repo

rted

were

gastrointestinal

disord

ers

(con

stipation,

drymou

th,

flatulence,

andna

usea

),ne

rvou

ssystem

disorders

(balan

cedisorder,som

nolence,

andhe

adache

),an

dgene

ral

disorders(fa

tigu

ean

dfeeling

hot).

PRM

does

notsign

ifican

tly

affect

sleeppa

rameters

inelde

rly.

Dolev

(201

1)See

Mirtaza

pinesection

Lem

oine

etal.(20

07)

55+

Primaryinsomnia

2-wksing

le-blind

placeb

oru

n-in

period

follow

edby

a3-wkRCTtrea

tmen

tpe

riod

.PRM

2mg/da

yvs.placeb

o.N

=17

0.

PRM

impr

oved

QOSmea

sured

byLSEQ

(222

.5vs.216

.5,

P=0.04

7).

Ninepa

tien

tsin

each

trea

tmen

tgrou

prepo

rted

AEs.The

most

common

repo

rted

AEswere

mild

.Diarrhe

aoccurred

inon

epa

tien

treceivingPRM

and

onepa

tien

treceivingplacebo.

PRM

iseffectiveat

redu

cing

symptom

sof

insomniain

theelde

rly.

Lem

oine

etal.(20

11)

20–80

Primaryinsomnia

6–12

moop

en-lab

elcontinua

tion

trial.PRM

2mg/da

y.N

=24

4.

Themea

n(+S.E.M

.)pe

rcen

tage

ofnigh

tspe

rweekscored

bythepa

tien

tsas

“good”

or“very

good

”increa

sedprogressively

withtrea

tmen

tdu

ration

.At

theplatea

ulevel,54

%–56

%of

nigh

tspe

rweekwerescored

as“good”

or“verygood

”(i.e.,

3.8nigh

ts/wk)

compa

redwith

26%

(i.e.,1

.8nigh

ts/wk)

atba

selin

e(P

,0.00

1),w

hich

was

maintaine

dthroug

hout

trial.

PRM

discon

tinu

ationev

enafter12

mowas

not

associated

withAEs,

withd

rawal

symptom

s,or

supp

ressionof

endo

geno

usmelaton

inpr

oduc

tion

.Most

common

repo

rted

even

tswereph

aryn

gitis(12.4%

)an

dba

ckpa

in(11.8%

).

PRM

iseffectiveat

redu

cing

symptom

sof

insomnia

aslong

-term

trea

tmen

t.

Lem

oinean

dZisa

pel(201

2)55

+Primaryinsomnia

Postho

can

alysis

ofpo

oled

antihy

perten

sive

drug

-trea

tedsu

bpop

ulations

from

four

rand

omized

,do

uble-

blindtrials

ofPRM

and

placeb

ofor3wk.

N=58

9.

Bytheen

dof

the6-mo

trea

tmen

tpe

riod

,mea

nssu

bjective

impr

ovem

entin

patien

ts’ev

aluated

SOL

was

sign

ifican

tlyhigh

erwith

PRM

(25.89

minutes)

than

withplaceb

o(7.54minutes)

P=0.02

.

Rateof

AEsnormalized

per

100pa

tien

t-wee

kswas

lower

forPRM

(3.66)

than

for

placeb

o(8.53).

PRM

isefficaciou

san

dsa

fein

prim

aryinsomnia

patien

tstrea

tedwith

antihyp

ertensive

drugs

Luthringe

ret

al.(20

09)

55+

Primaryinsomnia

2-wksing

le-blind

placeb

oru

n-in

follow

edby

3-wkRCT

ofPRM

2mg/da

yfor3wk

follow

edby

a3-wk

withd

rawal

period

.N

=40

PRM

grou

phad

sign

ifican

tly

shorterSOL(9

min;P

=0.02

)compa

redwiththeplaceb

ogrou

pan

dscored

sign

ificantly

better

intheCriticalFlicke

rFusionTest(P=0.00

8)witho

utne

gatively

affectingsleep

structurean

darchitecture.

Halfof

thepa

tien

tsreported

substantialim

provem

entin

QOSat

homewithPRM

compa

redwith15

%with

placebo(P

=0.01

8).N

oreboun

deffectswereobserved

during

withd

rawal

AEswerereported

by11

patien

tsin

each

treatm

entgrou

p.The

mostcom

mon

AEwas

headache,

repo

rted

byfour

patien

tsin

thePRM

grou

pan

dthreein

theplaceb

ogrou

p.No

sign

ificant

diffe

rencein

the

incide

nceof

AEs.

PRM

was

effectivein

redu

cing

symptom

sof

insomnia.

(con

tinued

)


TABLE

4—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Otm

aniet

al.(200

8)55

+Hea

lthy

participan

tsRCT

crossove

rstud

y.PRM

2mg,

zolpidem

10mg,

PRM

+zolpidem

vs.placeb

o.Effects

onps

ycho

motor

func

tion

s,mem

oryrecall,

anddr

ivingsk

ills

were

assessed

at1,

4han

dmorning

follow

ing

administration.

N=16

.

Amain‘‘treatmen

t’’effect

was

foun

dforallva

riab

les(P

,0.05

)Zo

lpidem

sign

ifican

tly

increa

sedseda

tion

compa

red

withplaceb

oat

1hou

r(P

=0.00

11,P,

0.00

01,

resp

ective

ly)an

d4hou

rspo

stdo

sing

(P,

0.00

01for

both)an

dcompa

redwith

PRM

at1hou

r(P

=0.03

,P,

0.00

01,respe

ctively)

and

4hou

r(P

=0.01

5forbo

th).

N/A

PRM

does

not

hav

esign

ifican

tcogn

itive

adve

rseeffectsin

the

elde

rly.

Wad

eet

al.(20

07)

55–80

Primaryinsomnia

2-wksing

le-blind

placeb

oru

n-in

period

follow

edby

a3-wkRCTtrea

tmen

tpe

riod

.PRM

2mg/da

yvs.placeb

o.N

=35

4.

PRM

impr

oved

qualityof

sleep

mea

suredby

LSEQ

(222

.5vs.216

.5,P

=0.04

7).

24%

and21

%of

patien

tsin

the

resp

ective

PRM

andplaceb

ogrou

psrepo

rted

AEs.

Most

common

lyrepo

rted

effects

werenas

opharyn

gitisan

dhe

adache

ormigraine.

PRM

iseffectiveat

redu

cing

symptom

sof

insomniain

theelde

rly.

Wad

eet

al.(20

10)

18–80

Primaryinsomnia

2-wksing

le-blind

placeb

oru

n-in

period

follow

edby

3-wkRCTof

PRM

2mg/da

yvs.placeb

o;26

-wkex

tens

ion

stud

ywith2wkof

sing

le-

blindplaceb

oru

n-ou

t.N

=79

1

PRM

inpa

tien

tswithlow

endo

geno

usmelaton

inrega

rdless

ofag

edidnot

impr

oveSOL

compa

red

withplaceb

o,whe

reas

PRM

sign

ifican

tlyredu

cedSOL

compa

redwithplaceb

oin

elde

rlypa

tien

tsrega

rdless

ofmelaton

inleve

ls(2

19.1

vs.21.7min;P

=0.00

2).

AE

ratesweresimilar

betw

een

PRM

andplaceb

ogrou

ps.

34.5%

and35

.9%

ofresp

ective

PRM-an

dplaceb

o-trea

tedpa

tien

tsrepo

rted

anyAE

duringthe

trea

tmen

tpe

riod

.In

extens

ionpe

riod

,73

.8%

and

76.8%

ofPRM-an

dplaceb

o-trea

tedsu

bjects

repo

rted

any

AE.Mostcommon

even

tswerenas

opharyn

gitis,

arthralgia,diarrh

ea,

resp

iratorytractinfections

,an

dhea

dach

e.

PRM

iseffectiveat

redu

cing

symptom

sof

insomniain

theelde

rly.

The

resu

lts

demon

strate

short-

and

long

-term

efficacy

and

safety

ofPRM

inelde

rly

insomniapa

tien

ts.Low

melaton

inpr

oduc

tion

rega

rdless

ofag

eis

not

useful

inpr

edicting

resp

onsesto

melaton

intherap

yin

insomnia.

Wad

eet

al.(20

14)

52–85

Mildto

mod

erate

Alzheimer’s

diseas

e,withan

dwithou

tinsomnia

comorbidity

2-wksing

le-blin

dplaceb

orun-in

follo

wed

by24

-wkRCTan

d2-wkplaceb

orun-ou

tpe

riod

.PRM

2mg/da

yvs.p

lacebo

.N

=80

.

Patientstrea

tedwithPRM

(24wk)

hadsign

ifican

tly

better

cogn

itivepe

rforman

cethan

thosetrea

tedwith

placeb

o,as

mea

suredby

the

IADL(P

=0.00

4)an

dMMSE

(P=0.04

4).M

eanADAS-C

ogdidnot

differ

betw

eenthe

grou

ps.ThePSQIglob

alscoreim

prov

edin

PRM

(21.62

[2.74],P

=0.00

4)bu

tno

tplaceb

ogrou

p(0.74

[2.52],P

=0.13

9)

AE

ratesweresimilar

betw

een

PRM

andplaceb

ogrou

ps.

82.1%

ofPRM

patien

tsrepo

rted

AEsvs.67

.6%

ofplaceb

o-trea

tedpa

tien

ts.

Add

-onPRM

has

positive

effectson

cogn

itive

func

tion

ingan

dsleep

maintenan

cein

AD

patien

tscompa

redwith

placeb

o,pa

rticularly

inthosewithinsomnia

comorbidity.

212 Atkin et al.

with an affinity 3–16 times higher than that of melato-nin (Kato et al., 2005). Its affinity for MT2 is eight timeslower than its affinity for MT1. This binding profiledistinguishes ramelteon from melatonin and tasimel-teon, which both display more affinity for the MT1

receptor than the MT2 receptor (Lavedan et al., 2015).The hypnotic effect of ramelteon is mediated by itspotent, long-lasting agonism of themelatonin receptors,because it does not exhibit affinity for benzodiazepinereceptors, dopamine receptors, opiate receptors, ionchannels, and does not affect the activity of variousenzymes (Kato et al., 2005) (Table 1). While studies inrats and monkeys confirm that ramelteon reduces timeto sleep onset without affecting total sleep time(Yukuhiro et al., 2004; Fisher et al., 2008), ramelteonincreases total sleep time in cats (Miyamoto et al., 2004).2. Indications. Ramelteon is FDA-approved for the

treatment of insomnia characterized by difficulty withsleep onset (US FDA, 2010a). Notably, the EuropeanMedicines Agency initially rejected Takeda Pharma-ceutical Company’s application (filed inMarch 2007) forlack of efficacy. Later, in September 2008, the companywithdrew their Marketing Authorization Application tothe Committee for Medicinal Products for Human Use(CHMP). The CHMP was concerned that the companyhad not demonstrated the effectiveness of ramelteon,because only one aspect of insomnia, the time to fallasleep, had been assessed in the trials (EuropeanMedicines Agency, 2008b). Furthermore, only one ofthe three studies that had been carried out in thenatural setting found a significant difference in thetime taken to fall asleep between patients takingramelteon and those taking placebo, and this differencewas considered too small to be clinically relevant. Whenother aspects of sleep were considered, ramelteon didnot have any effect (Kuriyama et al., 2014). The CHMPwas also concerned that Takeda had not demonstratedthe long-term effectiveness of ramelteon (EuropeanMedicines Agency, 2008b). Clinical studies examiningthe hypnotic effects of ramelteon are detailed in Table 5.3. Pharmacokinetics. At a dose range of 4–64 mg,

ramelteon undergoes rapid, high first-pass metabolismand exhibits linear pharmacokinetics (US FDA, 2010a).However, the drug shows substantial intersubject var-iability inmaximal serum concentration and area underthe concentration curve. Median peak concentrationoccurs at about 0.75 hours after fasted oral administra-tion. Although total absorption is at least 84%, absolutebioavailability is only 1.8% because of extensive first-pass metabolism (US FDA, 2010a). It has a half-life ofabout 1–2.6 hours. CYP1A2 is the major liver enzymeinvolved in the hepatic metabolism of ramelteon, al-thoughCYP2C andCYP3A4 are also involved to a lesserdegree: the drug is extensively transformed to itshydroxylated M-II metabolite, with serum AUC valuesthat average approximately 30 times those of the parentdrug (Greenblatt et al., 2007). It has been argued that

M-II, with its longer half-life and greater systemicexposure, may contribute significantly to the hypnoticeffect of ramelteon: M-II has been shown to bind tohuman MT1 and MT2 receptors, although with loweraffinity (Ki: 114 and 566 pmol/l for MT1 and MT2,respectively) (Nishiyama et al., 2014). Taking ramelteonwith a high-fat meal changes its pharmacokinetics; thearea under the concentration curve for a single 16mgdoseis 31% higher, whereas maximal concentration is 22%lower than when administered in a fasted state (US FDA,2010b). For this reason, the US FDA does not recommendtaking ramelteon after a high-fat meal. Moreover, clear-ance is significantly reduced in the elderly,

4. Results in Insomnia Disorder. Two meta-analyses found ramelteon effective at reducing sub-jective sleep latency time in primary insomnia (Liu andWang, 2012; Kuriyama et al., 2014). The first studyanalyzed 4055 patients (Liu and Wang, 2012) and thesecond analyzed 5812 patients (Kuriyama et al., 2014).One, a pooled analysis of four trials comparing ramel-teon to placebo, found that active treatment reducedsubjective sleep latency by 24.22 minutes, 95% confi-dence interval 25.66 to 22.77 minutes (P , 0.00001)(Liu and Wang, 2012). The other had similar results forsubjective sleep latency reduction, although it pooledresults from 12 studies:24.30 minutes, 95% confidenceinterval 27.01 to 21.58 minutes (Q = 23.64; df = 11)(Kuriyama et al., 2014). However, it did not find thatramelteon increased total sleep time significantly morethan placebo (Kuriyama et al., 2014).

5. Conclusion. A summary of the effects of ramel-teon on sleep architecture is presented in Table 2. Thereis strong evidence that ramelteon is effective in thetreatment of insomnia disorder characterized by diffi-culty with sleep onset, based on two meta-analyses (Liuand Wang, 2012; Kuriyama et al., 2014).

D. Tasimelteon

1. Mechanism of Action. Tasimelteon displays com-parable potency to melatonin at the MT1 receptor,whereas its affinity for MT2 is 2.1–4.4 times greater thanits affinity for MT1 (Lavedan et al., 2015). Its agonism atthese receptors is selective, as it lacks any other signif-icant interactions with receptors or enzymes (Table 1).

2. Indications. Tasimelteon is the first FDA-approved treatment of non-24-hour sleep-wake disorder(non-24), for which it was granted orphan drug status.Initially, Vanda Pharmaceuticals evaluated the efficacyof tasimelteon in the treatment of insomnia in phase IIand phase III studies (Vanda Pharmaceuticals Inc.,2008; Feeney et al., 2009), but the compound has onlyreceived regulatory approval for the treatment of non-24. Clinical studies examining the hypnotic effects oframelteon are detailed in Table 6.

3. Pharmacokinetics. The pharmacokinetics of tasi-melteon is linear over dose ranges from3 to 300mg,with anabsolute oral bioavailability of 38.3%and amean half-life of


TABLE

5Sum

maryof

stud

iesas

sessingtheeffectsof

ramelteon

(RMT)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Erm

anet

al.

(200

6)18

–64

Chronicpr

imary

insomnia

Five-pe

riod

crossove

rRCT.RMT

4vs.8vs.

16vs.32

mg/da

yvs.

placeb

o.N

=10

7.

PSG

LPS(m

inute)was

37.7

for

placeb

ovs.24

.0forRMT

4mg/

day,

P,

0.00

1,vs.2

4.3forRMT

8mg/da

y,P,

0.00

1,vs.2

4.0for

RMT

16mg/da

y,P

,0.00

1,vs.

22.9

forRMT

32mg/da

y,P

,0.00

1.P

,0.00

1forov

erall

effect.

Nodifferen

cein

numbe

ror

type

ofAEsbe

tweenactive

trea

tmen

tan

dplaceb

ogrou

p.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

Goone

ratne

etal.(20

10)

#60

Obs

tructivesleep

apnea

4-wkRCT.RMT

8mg/

dayvs.placeb

o.N

=21

.

Objective

polysomno

grap

hicSOL

(minute)

was

20.4

623

.2at

baselinein

theRMT

grou

pan

d9.76

10.3

aftertrea

tmen

t.In

theplaceb

ogrou

p,ob

jectiveSOL

was

16.6

617

.5at

baseline

and

34.4

630

.7aftertrea

tmen

t.For

betw

eengrou

pscompa

rison:

P=0.00

8.Subjective

SOL

was

notsign

ifican

tlyim

prov

ed.

Fou

rAEsoccu

rred

inRMT

arm

andtw

oin

placeb

oarm;n

onejudg

edrelatedto

trea

tmen

t.

RMTmay

beeffectiveat

redu

cingsymptom

sof

insomniain

olde

rad

ults.

Koh

saka

etal.

(201

1)20

–65

Chr

onic

prim

ary

insomnia

Crossov

erRCT(five

period

sof

2nigh

tsea

ch).RMT4vs.8

vs.

16vs.32

mg/da

yvs.

placeb

o.N

=65

.

LPS(m

inute)was

29.026

28.55

forRMT

4mg/da

y,22

.126

18.16forRMT

8mg/da

y,28

.17

629

.40forRMT

16mg/da

y,24

.376

32.79forRMT

32mg/

day,

and35

.276

40.68for

placeb

o.Differenc

esbe

tween

trea

tmen

tan

dplaceb

owereon

lysign

ifican

tforRMT8an

d32

mg/

day.

How

ever,the

line

arPva

lue

tren

dwas

:P

=0.00

46.

The

numbe

rof

patien

tswith

anAE

was

higher

inthe

16an

d32

mg/da

ythan

withplaceb

oan

dthe4an

d8mg/da

ydo

ses.

The

most

common

AEswere

somno

lenc

e,he

adache

,malaise,an

ddizziness.

RMT

8an

d32

mg/da

yareeffectiveat

redu

cingsymptom

sof

insomnia.

Kur

iyam

aet

al.

(201

4)18

–93

Chr

onic,pr

imary,

orps

ycho

physiological

insomnia;bipo

lar

disord

er;insomnia

associated

with

obstru

ctivesleep

apnea

Systematic

review

and

meta-an

alysis

ofplaceb

o-controlled

RCTs.

N=58

12.

RMT

was

sign

ifican

tlyas

sociated

withredu

cedsu

bjective

SOL

andim

prov

edQOS.It

was

not

associated

withincrea

sed

subjective

totalsleeptime.

Only

sign

ifican

tAE

was

somno

lenc

e.Nodifferen

cein

occu

rren

ceof

othe

rAEs

betw

eenRMTan

dplaceb

o.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

Liu

andWan

g(201

2)18

andov

erDSM-IV

prim

ary

chronic

insomnia

Systematic

review

and

meta-an

alysis

ofplaceb

o-controlled

RCTs.

N=40

55

Significant

impr

ovem

ents

inself-

repo

rted

andpo

lysomno

grap

hic

SOL,T

ST,latency

toREM.No

impr

ovem

entin

percen

tage

ofREM.

RMTwas

not

associated

with

ahighrisk

ratioof

any

freq

uent

AEscompa

red

withplaceb

o.How

ever,

thereweresign

ifican

tly

moresu

bjective

repo

rtsof

atleas

ton

eAE

withRMT.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

May

eret

al.

(200

9)18

–79

Chr

onic

prim

ary

insomnia

6-moRCT.RMT

8mg/

dayvs.placeb

o.N

=45

1.

RMT

cons

istently

redu

cedLPS

compa

redwithba

seline

and

compa

redwithplaceb

oas

mea

suredby

objective

polysomno

grap

hy.R

MTredu

ced

LPS(m

inute)

from

70.75at

baseline

to32

.02at

week1.

Sim

ilar

effectswereob

served

atea

chfollow

up.

Incide

nceof

AEswas

similar

betw

eenRMT

(51.8%

)an

dplaceb

o(50.7%

)grou

ps.

Eightpa

tien

tsin

RMTan

d10

patien

tsin

placeb

odiscon

tinued

dueto

anAE.

Leu

kope

niaoccu

rred

inon

eRMT-treated

subject

andwas

judg

edas

possibly

trea

tmen

trelated.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia

over

the

cour

seof

6mo. (con

tinued

)

214 Atkin et al.

TABLE

5—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

McE

lroy

etal.

(201

1)18

–65

Bipolar

Idisord

er8-wkRCT.8mg/da

yRMT

vs.placeb

o.N

=21

.

RMTan

dplaceb

oan

dsimilar

rates

ofredu

ctionin

symptom

sof

insomnia,

man

ia,an

dglob

alseve

rity

ofillness.

RMT

was

associated

withim

prov

edde

pressive

symptom

s.Pittsbu

rghIn

somniaRating

Scale

totalscoredifferen

cefrom

baseline

tofina

lvisit:placeb

o,269

.3vs.R

MT,2

54.2,P

=0.46

.

Onepa

tien

tof

21whowere

rando

mized

withdr

ewdu

eto

seda

tion

(RMT

grou

p).

Nopa

rticipan

tex

perien

ced

aseriou

sAE.S

malls

ample

size

limitsab

ilityto

detect

mea

ning

fuldifferen

cesin

theoccu

rren

ceof

AEs.

RMT

may

not

beeffectiveat

redu

cing

symptom

sof

insomniain

bipo

larI

disord

er.

NCT#0

0755

495

18–80

Primaryinsomnia

byDSM-IV-TR

5-wkRCT.RMT

8mg/

day+do

xepin3mg/

dayvs.R

MT8mg/da

yvs.do

xepin3mg/da

yvs.placeb

o.N

=47

2.

RMT8mg/da

y+do

xepin3mg/da

ywas

sign

ifican

tlysu

perior

toplaceb

oat

redu

cingLPSat

wee

k1,

P,

0.00

1.How

ever,at

week

3,P

=0.40

0,an

dat

wee

k5,

P=

0.12

2.RMT

8mg/da

y+do

xepin

3mg/dwas

sign

ifican

tly

supe

rior

toplaceb

oat

increa

sing

TSTat

alltim

epo

ints:P

,0.00

1at

week1,

P=0.01

7at

week3,

and0.03

6an

dweek5.

The

ratesof

AEsweresimilar

amon

galltrea

tmen

tgrou

ps:28

.1%

ofRMT

+do

xepin,3

0.8%

fordo

xepin,

35.9%

forRMT,36

.6%

for

placeb

o.Mostrepo

rted

AEs

weresomnolen

ce(4.9%)

andhe

adache

(4.5%),with

somno

lenc

eoccu

rringwith

thegrea

test

incide

ncein

theRMT

+do

xepingrou

p(8.8%).

RMT

+do

xepinis

effectiveat

redu

cing

symptom

sof

insomnia.

Sub

jective

sleepqu

ality

impr

oved

morewith

RMT

+do

xepinthan

withRMT

alon

eov

er5wkof

trea

tmen

t.

Rothet

al.

(200

6)64

–93

Primaryinsomnia

35-nightRCT.RMT

4mg/da

yvs.8

mg/da

yvs.placeb

o.N

=82

9.

LPS(m

inute)at

wee

k1was

70.2

forRMT

4mg/da

yvs.78

.5min

forplaceb

o,P=0.00

8;it

was

70.2

forRMT

8mg/da

yvs.78

.5forplaceb

o,P=0.00

8.RMTalso

sign

ifican

tlyincrea

sedTST

and

rebo

undinsomnia

orwithdr

awal

effectswereno

tob

served

follow

ingdiscon

tinu

ation.

Incide

nceof

AEswas

similar

amon

galltrea

tmen

tgrou

ps.In

cide

nce

ofan

yAE:51

.5%

ofplaceb

ogrou

p,54

.8%

ofRMT4mg/

day,

58.0%

ofRMT

8mg/

day.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

Rothet

al.

(200

7)65

–83

Chr

onic

prim

ary

insomnia

9-wk,

three-pe

riod

crossove

rRCT

trial

withtrea

tmen

tad

ministeredfor

2nightspe

rtrea

tmen

t.RMT

4vs.

8mg/da

yvs.placeb

o.N

=10

0.

SOL

(minute)was

28.7

forRMT

4mg/da

yvs.38

.4forplaceb

o,P,

0.00

1;30

.8forRMT

8mg/

dayvs.38

.4forplaceb

o,P

=0.00

5.TST

andSE

werealso

sign

ifican

tlyim

prov

ed.

Incide

nceof

AEscons

idered

trea

tmen

t-relatedwas

placeb

o7%

,RMT4mg/da

y11

%,a

ndRMT

8mg/da

y5%

.Noev

iden

ceof

nex

t-da

yps

ycho

motor

orcogn

itiveeffects.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

Uch

imur

aet

al.

(201

1)Mea

n:4

8.8;

S.D

.:17

.2Chronic

insomnia

RCT.RMT

4vs.8mg/

dayvs.placeb

ofor

2wkfollow

edby

dose

escalation

to8vs.

16vs.4mg/da

y,resp

ective

ly,for

2wk.

N=11

43.

LSmea

nweeklysu

bjective

SOL

(minute)

atweek1:

RMT

4mg/

daywas

notsign

ifican

tly

supe

rior

toplaceb

o,P

=0.93

15.

RMT

8mg/da

ywas

not

sign

ifican

tlysu

perior

toplaceb

o,P=0.09

05.

42.1%

intheplaceb

o/4mg/

daygrou

p,42

.5%

inthe4/

8mg/da

ygrou

pan

d41

.8%

inthe8/16

mg/da

ygrou

prepo

rted

atleas

ton

etrea

tmen

t-em

erge

ntAE

Theincide

ncesof

AEs

amon

gthetrea

tmen

tgrou

pswerecompa

rable,

andnodo

se–resp

onse

relation

shipswere

observed

.

RMT

may

not

beeffectiveat

redu

cing

symptom

sof

insomnia.

(con

tinued

)


TABLE

5—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Uch

iyam

aet

al.

(201

1)20

–85

Chronic

insomnia

4-wkRCT.RMT

8mg/

dayvs.placeb

ofor

2wkfollow

edby

2-wk

placeb

oru

n-ou

tpe

riod

tomon

itor

rebo

undinsomnia.

N=98

7.

RMT

was

sign

ifican

tlysu

perior

toplaceb

oat

redu

cing

SOLat

week

1bu

tinsign

ifican

tlysu

perior

toplaceb

oat

week2.

LSmea

n(in

minute)

forRMT

was

61.156

0.97

atweek1vs.65

.696

0.97

forplaceb

o.

Noev

iden

ceof

rebo

und

insomnia.2.7%

ofRMT

grou

pan

d2.3%

ofplaceb

ogrou

pdiscon

tinued

dueto

AEs.

Themostcommon

reas

onin

both

grou

pswas

nas

opharyn

gitis.

One

seriou

sad

verseeffect

occu

rred

inRMT

grou

p,a

road

accide

nt.15

hafter

taking

drug

.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia

after1wkof

trea

tmen

t.

Wan

g-Weiga

nd

etal.(20

11)

18–64

Chronic

insomnia

3-wkRCT.RMT

8mg/

dayvs.placeb

o.N

=55

6.

For

mea

nsu

bjective

SOL

relative

toplaceb

o:week1-redu

ctionof

4.1min,P

=0.08

8.Week2:

redu

ctionof

2.8min,P

=0.25

8.Week3:

redu

ctionof

4.9min,P

=0.06

0.Nosign

ifican

tdifferen

cefrom

placeb

o.

Som

nolenc

eoccu

rred

in1.8%

ofplaceb

ogrou

pan

d4.4%

ofRMT

grou

p.The

prop

ortion

ofsu

bjects

with

anytrea

tmen

t-relatedAEs

was

similar

betw

een

grou

ps(placebo

15.4%,

ramelteon

16.5%).

RMT

8mg/da

ymay

not

beeffectiveat

redu

cingsymptom

sof

insomnia.

Zammit

etal.

(200

7)18

–64

Primaryinsomnia

5-wkRCT.RMT

8vs.

16mg/da

yvs.p

lacebo

.N

=40

5.

LPS(m

inute)at

wee

k1was

32.2

forRMT

8mg/da

yvs.28

.9for

RMT

16mg/da

yvs.47

.9for

placeb

o,P

,0.00

1;sign

ifican

tim

prov

emen

tsweremaintaine

dat

weeks

3an

d5.

Noev

iden

ceof

next-day

pharmacolog

icresidu

aleffects.

Noev

iden

ceof

rebo

undinsomnia

follow

ingdiscon

tinu

ation

ofRMT.Mostcommon

AE

inallg

roups

was

hea

dach

e.

RMT

iseffectiveat

redu

cingsymptom

sof

insomnia.

Zammit

etal.

(200

9)$65

Insomnia

Thr

ee-w

aycrossove

rRCT.RMT

8mg/da

yvs.zolpidem

10mg/

dayvs.placeb

o.N

=33

.

While

zolpidem

sign

ifican

tly

impa

ired

performan

ceon

the

sens

oryorga

niza

tion

test,turn

time,

andturn

sway

(P,

0.00

1forall),R

MT

didno

tpr

oduc

ean

ydifferen

cesfrom

placeb

o.Im

med

iate

recallde

clined

sign

ifican

tlywithzolpidem

(P=

0.00

2)while

itwas

similar

toplaceb

oforRMT.

N/A

RMT

didnot

impa

irmiddle-of-the

-night

balanc

e,mob

ility,

ormem

oryin

olde

rad

ults

relative

toplaceb

o

216 Atkin et al.

1.360.4hours (USFDA,2014b). Like for ramelteon, takingtasimelteon with a high-fat meal lowers Cmax (by 44%) anddelaysTmax (by 1.75 hours) compared with the fasted state.For this reason, the FDA recommends that the drug not betaken with food. CYP1A2 and CYP3A4 are the majorisoenzymes associated with its hepatic metabolism, andmajor metabolites have 13-fold or less activity at melatoninreceptors (US FDA, 2014b). Exposure to tasimelteonincreases approximately twofold in the elderly comparedwith nonelderly adults and in women approximately 20%–

30% compared withmen. Smokers had approximately 40%lower exposure to tasimelteon than nonsmokers.4. Results in Healthy Volunteers. Two short RCTs of

tasimelteon in healthy volunteers have been published: aphase II RCT and a phase III RCT (again in healthyvolunteers) of the drug as a treatment of transient in-somnia induced by shifted sleep (Rajaratnam et al., 2009).In the phase II trial, the individuals were monitored forseven nights: three at baseline, three after a 5-houradvance of the sleep-wake schedule, and one night aftertreatment. In the phase II RCT, tasimelteon reduced sleeplatency and increased sleep efficiency relative to placeboand shifted the plasma melatonin rhythm to an earlierhour. The phase III study had similar positive results.5. Results in Insomnia Disorder. There were no

published studies of tasimelteon in patients diagnosedwith insomnia disorder. However, one clinical trial inpatients with primary insomnia (NCT#00548340), whichwas published only as an abstract, found a significantmean change in latency to persistent sleep [standarderror]: 45.0 [2.965] for tasimelteon 20 mg/day versus 46.4[2.954] for tasimelteon 50 mg/day versus 28.3 [3.020] forplacebo (Vanda Pharmaceuticals Inc., 2014).6. Results in Other Conditions. Other trials were

conducted in patients diagnosed with non-24 sleep-wake disorder (Lockley et al., 2015), for which tasimel-teon has gained FDA approval as an orphan drug(Dhillon and Clarke, 2014). The investigators foundthat tasimelteon significantly improved entrainment.7. Conclusion. A summary of the effects of tasimel-

teon on sleep architecture is presented in Table 2. Thereis poor-quality evidence for the use of tasimelteon in thetreatment of insomnia disorder, based on two studies inhealthy volunteers (Rajaratnam et al., 2009).

V. Orexin Receptor Antagonist Drugs

A. Suvorexant

1. Mechanism of Action. Suvorexant’s effect as ahypnotic is attributable to its selective antagonism ofthe orexin receptors OX1R and OX2R (Winrow et al.,2011; Yin et al., 2016) (Table 1). In vitro assay panelsdemonstrate suvorexant’s selectivity for the orexinreceptors over 170 known receptors and enzymes (Coxet al., 2010). In mice, suvorexant has been shown toselectively increase REM sleep in the first 4 hours afterdosing (Hoyer et al., 2013).

2. Indications. Suvorexant is FDA approved for thetreatment of insomnia characterized by difficulty withsleep onset and/or sleep maintenance at the doses of 5,10, 15, and 20 mg/day but not the higher doses studiedin the clinical trials (US FDA, 2014a). The FDA chosenot to approve suvorexant at the 30 or 40 mg/day dosesstudied in the phase III trials because of safety concerns,particularly next-day driving impairment at doses of 20mg/d and higher (US FDA, 2014a). There were also a fewreports of sleep paralysis and hallucinations, unconsciousnighttime behaviors, and narcolepsy-like events amongdrug-treated subjects. Clinical studies examining thehypnotic effects of suvorexant are detailed in Table 7.

3. Pharmacokinetics. Exposure to suvorexantdoesnotincrease linearly over the dosage range 10–80 mg becausethe drug is absorbed less at higher doses (US FDA, 2014a).The mean bioavailability of suvorexant 10 mg is 82% andingestion of the drug with food does not meaningfully affectAUC or Cmax but does delay Tmax by approximately 1.5hours. Steady-state pharmacokinetics are achieved in3 days, and the mean half-life of the drug is 12 hours(95% confidence interval: 12–13). Exposure to suvorexant ishigher inwomen than inmen,withAUCincreased17%andCmax increased 9%, for suvorexant 40 mg.

4. Results in Insomnia Disorder. There are twosystematic reviews of suvorexant as a treatment ofprimary insomnia (Citrome, 2014; Kishi et al., 2015).Although both reviews analyze the same four phase IIand phase III trials in insomnia patients, one of themdiffers from the other by following PRISMA reportingguidelines (Kishi et al., 2015). Both systematic reviewsanalyzed the same four phase II and phase III RCTs andcame to similar conclusions: that suvorexant was safeand effective for the treatment of insomnia. Suvorexantimproved subjective total sleep time (weighted meandifference = 220.16, 95% confidence interval = 225.01to 215.30, 1889 patients, three trials) and subjectivetime to sleep onset (weighted mean difference = 27.62,95% confidence interval = 211.03 to 24.21, 1889 pa-tients, three trials) (Kishi et al., 2015).

Subgroup analysis of approved (15 and 20 mg/day)versus unapproved (30 or 40 mg/day) found that forefficacy, the number needed to treat values versusplacebo of suvorexant 40 and 30 mg/day and that ofthe 20 and 15 mg/day doses were the same: 8 (Citrome,2014). However, for adverse effects, there were numberneeded to harm values versus placebo of 13 for thehigher doses and 28 for the lower doses, indicating thatthe lower doses are better tolerated. Although the othersystematic review did not specifically analyze approvedversus unapproved doses, the authors performed ananalysis in which they excluded the higher doses fromthe primary outcomes and found that suvorexantremained superior to placebo in subjective total sleeptime and subjective time to sleep onset at 1 month(Kishi et al., 2015). Suvorexant was found to have anefficacy similar to the benzodiazepines, ramelteon, and


TABLE

6Sum

maryof

stud

iesas

sessingtheeffectsof

tasimelteon

(TMT)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Johnsa

and

Nev

ille

(201

4)Heterog

eneous

Heterog

eneous

Rev

iew

offour

RCTs.

Inon

eph

aseII

trial,sign

ifican

tsh

ifts

incircad

ianrh

ythm

wereob

served

only

forTMT

100mg/da

y.In

aph

aseIII

trial,LPSwas

sign

ifican

tly

impr

oved

intheTMTgrou

prelative

toplaceb

o.The

SET

andRESETtrials

both

found

TMTto

sign

ifican

tlyim

prov

een

trainm

entin

non-24

-hou

rsleep-wak

edisord

erpa

tien

ts.

Frequ

ency

andseve

rity

ofAEsweresimilar

across

trea

tmen

tgrou

ps.Most

common

AEswere

somnolen

cean

dhe

adache

.

TMT

iseffectiveat

redu

cing

symptom

sof

non-24

-hou

rsleep-wak

edisord

er.

Lockley

etal.

(201

5)18

–75

Total

blindn

esswith

non-24-hou

rsleep-

wak

edisord

er

TwoRCTs,

SET

(26wk,

N=84

)an

dRESET

(19wk,

N=20

).TMT

20mg/da

yvs.p

lacebo

.

TMT

sign

ifican

tlyim

prov

eden

trainm

ent,althou

ghthe

effect

didnot

last

after

discon

tinu

ation.

Nosign

ifican

tdifferen

cein

thediscon

tinu

ationrate

dueto

AEsbe

twee

nthe

TMT

(6%)an

dplaceb

o(4%)grou

ps.Hea

dach

ean

dincrea

sedalan

ine

aminotrans

ferase

occu

rred

inmorepa

tien

tsreceivingTMTthan

placeb

o.

TMT

iseffectiveat

redu

cing

symptom

sof

non-24

-hou

rsleep-wak

edisord

er.

NCT#0

0548

340

18–65

Primaryinsomnia

5-wkRCT.TMT

20vs.

50mg/da

yvs.p

lacebo

.N

=32

1.

Statisticswereno

tcond

ucted.

Mea

nch

ange

inLPS[S.E.]

was

45.0

[2.965

]forTMT

20mg/da

y,46

.4[2.954

]for

TMT50

mg/da

y,an

d28

.3[3.020

]forplaceb

o.Mea

nch

ange

inTST

was

51.4

[4.794

],52

.0[4.775

],an

d39

.9[4.882

]forthesa

me

resp

ective

grou

ps.

Mostcommon

AEswere

nasoph

aryn

gitisan

dhe

adache

.

Statisticswereno

tcond

ucted.

Rajaratna

met

al.(20

09)

Phas

eII

RCT:

18–50

.Phas

eIII

RCT:21

–50

.

Phas

eII

RCT:hea

lthy

volunteers.Pha

seIII

RCT:hea

lthy

volunteers

with

indu

cedtran

sien

tinsomnia

TwoRCTs.

Pha

seII

RCT:T

MT10

vs.2

0vs.

50vs.1

00mg/da

yvs.

placebo.

N=39

.Pha

seIIIRCT:T

MT20

vs.

50vs.1

00mg/da

yvs.

placebo.

N=41

1.

Intheph

aseII

RCT,TMT

redu

cedSOL

andincrea

sed

SE

compa

redwithplaceb

o.In

theph

aseIIIstud

y,TMT

impr

oved

SOL,SE,an

dWASO.L

PSwas

sign

ifican

tlyredu

cedrelative

toplaceb

o:in

phas

eII

stud

y,TMT10

mg/da

y,P

=0.00

3;50

mg/da

y,P

=0.01

9;10

0mg/da

y,P=0.02

1.In

the

phas

eIIIstud

y,alldo

sesof

TMT,P

,0.00

1forredu

cing

LPS.

Rates

ofAEsweresimilar

betw

eenTMT

and

placeb

o.

TMT

iseffectiveat

redu

cing

symptom

sof

insomnia

inamod

elof

circad

ianrh

ythm

disord

ers.

218 Atkin et al.

TABLE

7Sum

maryof

stud

iesas

sessingtheeffectsof

suvo

rexa

nt(SVX)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Citrome(201

4)18

–87

Primaryinsomnia

Systematic

review

offour

phas

eII

andph

aseIII

RCTs.

LSmea

ndifferen

cefrom

placeb

oin

subjective

TST

atmon

th1(m

inute):18

.4,P

,0.00

1for

SVX15

or20

mg;

22.7,P

,0.00

1forSVX

30or

40mg.

LSmea

ndifferen

cefrom

placeb

oin

SOL

bypo

lysomno

grap

hyat

mon

th1(m

inute):29.1,

P,

0.00

1for

SVX

15or

20mg;

211

.4,

P,

0.00

1forSVX

30or

40mg.

Reb

oundinsomnia

and

withdr

awal

effectsnot

observed

aftertrea

tmen

tdiscon

tinu

ation.

Som

nolenc

eis

themost

common

AE.

SVX

iseffectiveat

redu

cing

symptom

sof

insomnia.

Highe

rdo

sesaremore

effectivebu

tmay

hav

ea

high

errisk

ofAEs.

Herringet

al.(201

2)18

–64

Primaryinsomnia

byDSM-IV

4-wkcrossove

rRCT.SVX

10vs.2

0vs.4

0vs.8

0mg/

day.

N=25

4.

Objective

ly-m

easu

redLPS

(minute)at

EOSwas

chan

ged

relative

toplaceb

o22.3[2

12.2,

7.5]

for10

mg/da

y,222

.3[232

.3,2

12.3]for

20mg/da

y,23.8

[213

.8,6

.3]for40

mg/da

y,29.5

[219

.7,0.7]for

80mg/da

y.How

ever,

ingene

ral,morerobu

steffectswere

observed

forSV

X40

and80

mg/da

yon

subjectiv

eSO

L,o

bjectiv

eTST

,an

dsubjectiv

eQOS.

10an

d20

mg/da

ysh

owed

similar

leve

lsof

adve

rse

effectsto

placeb

o,while

40an

d80

mg/da

yha

dincrea

sedad

verseeffects.

One

patien

treceiving

SVX

80mg/da

yhad

amildvisu

alha

lluc

ination

anddiscon

tinu

ed.Most

common

AEswere

somno

lenc

e,he

adache

,an

ddizziness.

SVX

iseffectiveat

redu

cing

symptom

sof

insomnia.

SVX

10an

d20

mg/da

yarebe

tter

toleratedthen

40an

d80

mg/da

y.

Herringet

al.(201

6)non

elde

rly

(18–

64)an

delde

rly($

65)

Primaryinsomnia

byDSM-IV-TR

Two3-moRCTsin

elde

rly

andno

n-elde

rlypa

tien

ts.

SVX

40/30mg/da

yvs.

SVX

20/15mg/da

yvs.

placeb

o.N

=10

21in

first

RCTan

dN

=10

19in

secondRCT.

Sub

jectiveSOL(m

inute)

differen

cebe

tweenSVX

40/30mg/da

yan

dplaceb

oat

mon

th3:

28.4

[212

.8,24.0]

intrial1,

213

.2[2

19.4,27.0]

intrial2.

Themostcommon

AE

that

was

increa

sedforSVXvs.

placeb

owas

nex

t-da

ysomno

lenc

e.

SVX

iseffectiveat

redu

cing

symptom

sof

insomnia.

SVX

40/30mg/da

ywas

supe

rior

toplaceb

oon

almostallsu

bjective

and

polysomnog

raph

yen

dpo

ints

inbo

thtrials;S

VX

20/15mg/da

ywas

supe

rior

toplaceb

oon

man

ysu

bjective

mea

sures.

Kishi

etal.(201

5)NS

Primaryinsomnia

byDSM-IV

Systematic

review

and

meta-an

alysis

offour

placeb

o-controlled

RCTs.

N=30

76.

Mea

npo

oled

(15an

d40

mg/da

y)differen

cebe

tweenSVX

and

placeb

oin

subjective

TST

atmon

th1(m

inute):220

.16

[225

.01,

215

.30].Mea

npo

oled

(15an

d40

mg/da

y)diffe

rence

betw

eenSV

Xan

dplaceboin

subjectiv

eTST

atmon

th1(m

inute):2

7.62

[211

.03,

24.21

].

Discontinua

tion

dueto

all-

cause,

inefficacy,

and

intolerabilitydidno

tdiffe

rbetw

eengrou

ps.S

VX

grou

pha

dhigh

erincidence

ofab

norm

aldreams,

somno

lence,

excessive

daytim

esleepine

ss,fatigue

,an

ddrymou

th.

SVX

iseffectiveat

redu

cing

symptom

sof

insomnia.

(con

tinued

)


sedating antidepressants at reducing symptoms of in-somnia (Kishi et al., 2015).

5. Conclusion. Asummary of the effects of suvorexanton sleep architecture is presented in Table 2. There isstrong evidence that suvorexant is effective at reducingsymptoms of insomnia disorder at doses 15–40 mg/day,based on two systematic reviews (Citrome, 2014; Kishiet al., 2015). Suvorexant exerts strong effects on increas-ing total sleep time. Lower doses may be preferred, perFDA guidelines, to minimize the risk of adverse effects.

VI. Antidepressant Drugs

Sedating antidepressants are commonly prescribed forinsomnia: one analysis found that they were prescribedmore often than the FDA-approved treatments for in-somnia in 2002 (Walsh, 2004; McCall, 2016). Trazodonewas the most commonly prescribed medication for in-somnia in 2002, with 34% more prescriptions than themost commonly prescribed FDA-approved treatment(Walsh, 2004). In fact, there were 5.28 million prescrip-tions for antidepressants for insomnia and only 3.4millionprescriptions for FDA-approved hypnotics (Walsh, 2004).

A. Amitriptyline

1. Mechanism of Action. Amitriptyline is a tricyclicantidepressant with strong effects as a serotonergicreuptake inhibitor [SERT Ki (nM) = 3.13] (Vaishnaviet al., 2004) and moderate effects as a norepinephrinereuptake inhibitor [NET Ki (nM) = 22.4] (Tatsumi et al.,1997). Indeed, serotonergic-norepinephrine reuptakeinhibitors lack hypnotic properties, and as thus, ami-triptyline’s hypnotic effects are attributable to its pro-file as an H1 and H2 receptor antagonist as well as a5-HT2A and 5-HT2C antagonist. Main molecular targetsof amitriptyline are summarized in Table 1.

2. Indications. Amitriptyline is FDA approved forthe treatment of major depressive disorder (Alphapharm,2012). Clinical studies examining the hypnotic effects ofamitriptyline are detailed in Table 8.

3. Pharmacokinetics. Amitriptyline is well-absorbedwith peakplasma concentrations occurringwithin 6 hoursof oral administration (Alphapharm, 2012). The meanhalf-life of amitriptyline is 22.4 hours, whereas the meanhalf-life of its active metabolite nortriptyline is 26 hours.Amitriptyline is 96% bound to plasma proteins, andundergoes extensive first-pass metabolism in the liver tonortriptyline viaN-demethylation mediated by CYP2C19(Rudorfer and Potter, 1999). Other liver enzymes involvedin its metabolism are CYP2D6 and CYP3A4 (RudorferandPotter, 1999).Genetic heterogeneity betweenpatientsaffects the concentration of the drug in the body, partic-ularly the ratio between amitriptyline and nortriptyline(Rudorfer and Potter, 1999).

4. Results in Insomnia Disorder. No studies ofamitriptyline as a treatment of insomnia disorder wereidentified.

TABLE

7—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Michelsonet

al.(20

14)

18+

Primaryinsomnia

byDSM-IV-TR

Yea

rlon

gRCTwitha

subs

eque

nt2-mo

rand

omized

discon

tinu

ationph

asein

which

participan

tsgive

nplaceb

oweresw

itch

edto

SVX

andvice

versa.

SVX

40mg/da

yforpa

tien

tsyo

unge

rthan

65,3

0mg/

dayforpa

tien

tsolde

rthan

65,o

rplaceb

o.N

=78

1.

Cha

ngein

subjective

SOL(m

inute)

atmon

th12

forSVX

was

226

.6[2

30.5,222

.7]vs.217

.0[2

22.6,211

.4]forplaceb

o,P=0.00

55.C

hang

ein

subjective

TST

(minute)at

mon

th12

was

60.5

[54.0,

66.9]forSVXvs.3

3.0

[23.7,

42.2]for

placebo,P,

0.0001.

Mostcommon

AE,

somno

lenc

e,repo

rted

for

13%

ofpa

tien

tsreceiving

SVX

vs.3%

ofthose

receivingplaceb

o.Fatiguean

ddr

ymou

thwerealso

increa

sedfor

SVX

vs.placeb

ogrou

ps.

SVX

iseffectiveat

redu

cing

symptom

sof

insomnia.

SVX

ispr

obab

lynot

associated

withrebo

und

insomnia

during

discon

tinu

ationafter1yr

oftrea

tmen

t.

Sunet

al.(201

3)18

–45

Hea

lthy

young

men

Fou

r-pe

riod

crossove

rRCT

follow

edby

afifthpe

riod

toas

sess

pharmacok

inetics.

SVX

10vs.50

vs.10

0mg/da

yN

=22

(com

pleted

19).

SVX50

and10

0mgde

crea

sedLPS

andWASO

andincrea

sedSE

andTST.

Allrepo

rted

adve

rseev

ents

weremild.

Themost

freq

uently

repo

rted

adve

rseev

ents

were

somno

lenc

e(20%

inthose

receivingSVX

100mg)

andhea

dach

e.

SVX

iseffectiveat

prom

otingsleepin

healthysu

bjects

witho

utkn

ownsleep

impa

irmen

ts

220 Atkin et al.

5. Other Results. Two studies of amitriptyline as atreatment of secondary insomnia were identified. Onestudy examined amitriptyline’s effect on sleep in healthyvolunteers when administered chronically (Hartmannand Cravens, 1973) and one study analyzed patients withopiate withdrawal insomnia (Srisurapanont and Jarusur-aisin, 1998). The study in healthy volunteers foundaltered sleep patterns in the group given amitriptylinecompared with placebo, with those given the drug dis-playing increased total sleep time, increasedSWS, and lessREM (“desynchronized” sleep) (Hartmann and Cravens,1973). The other study compared amitriptyline 50 mg/dayto lorazepam 1–4 mg/day in patients with opiate with-drawal insomnia, finding that although amitriptyline waslikely as effective as lorazepam at relieving insomniasymptoms, it may have been associated with a hangovereffect thenext day (Srisurapanont andJarusuraisin, 1998).

6. Conclusion. A summary of the effects of amitrip-tyline on sleep architecture is presented in Table 2.Based on amitriptyline’s effect in a study of healthyvolunteers (Hartmann and Cravens, 1973) of increasingtotal sleep time and its efficacy in opiate withdrawalinsomnia, there is weak evidence of its efficacy in thetreatment of insomnia disorder.

B. Mirtazapine

1. Mechanism of Action. Mirtazapine is classified asa noradrenergic and specific serotonergic antidepres-sant, because it enhances adrenergic and serotonergicneurotransmission in a manner distinct from otherclasses of drugs. Its effects as a sedative and as ahypnotic are attributable to its blockade of the hista-mine H1 receptor. By antagonizing a2-autoreceptors itincreases norepinephrine release; by antagonizing a2-het-eroreceptors it increases serotonin release, although itseffect on serotonergic systems is specific to 5-HT1A-medi-ated neurotransmission, because it also blocks the 5-HT2

and 5-HT3 receptors (Anttila and Leinonen, 2001) (SeeTable 1 for the list ofmirtazapine’smainmolecular targets).In mice, thermal hyperalgesia and sleep disturbance in amodel of neuropathic pain were nearly completely normal-ized by mirtazapine administration (Enomoto et al., 2012).

2. Indications. Mirtazapine is FDA approved for thetreatment of major depressive disorder in adults (USFDA, 2007b). Clinical studies examining the hypnoticeffects of mirtazapine are detailed in Table 9.

3. Pharmacokinetics. Mirtazapine is rapidly andcompletely absorbed and has a half-life of between20 and 40 hours, with women exhibiting significantlylonger elimination half-lives thanmen (mean half of life37 hours for women vs. 26 hours for men) (US FDA,2007b). Peak plasma concentration is reached within2 hours of administration, and the presence or absenceof food does not significantly affect its pharmacoki-netics. Plasma levels are linear to dose over a dose rangeof 15–80 mg. The drug is 85% bound to plasma proteins.The drug’s absolute bioavailability is about 50%, and

TABLE

8Summaryof

stud

iesas

sessingtheeffectsof

amitryptiline(A

MT)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Hartm

annan

dCrave

ns(197

3)21

–35

Hea

lthyvo

lunteers

1125

-night

crossove

rstud

y.AMT

50mg/da

yvs.placeb

ovs.

reserp

ine0.50

mg/da

yvs.

chlorp

romaz

ine50

mg/da

yvs.

chloralhyd

rate

500mg/da

yvs.

chlord

iazepo

xide

50mg/da

y.N

=14

.

TST

increa

sedforAMT

relative

toplaceb

othroug

hout

trial.SWS

increa

sedan

dSOL

decrea

sed

earlydu

ring

administration.

REMS(“de

sync

hron

ized

sleep”)

was

redu

cedthrough

outthe

trial,mostpr

ofou

ndly

inthe

firstfew

days

ofad

ministration.

Sub

jectsthem

selves

asfeeling

worse

inthemorning

during

AMT

trea

tmen

t.Rep

orts

offeelingsick

increa

sedforweeks

3an

d4on

andwee

ks1an

d2off

med

ication.

Rep

orts

ofun

usua

lps

ycho

logicfeelings

increa

sedin

week4on

med

ication.

AMTis

prob

ably

effectiveat

redu

cing

symptom

sof

insomnia.

Men

dlew

iczet

al.

(199

1)25

–68

Depressed

inpa

tients

Retrosp

ective

stud

ybe

fore

trea

tmen

twithAMT

andat

5-7

wkfollow

up.

AMT

(165

635

mg/da

y).N

=18

.

Marke

dsu

ppressionof

REM

sleep.

Increa

sein

stag

e1an

dstag

e2NREM

slee

pan

dnoch

ange

sin

SWSan

dlatenc

yto

sleep

onset.

Not

assessed

.AMT

indu

cesalargeREM

sleepsu

ppressionin

depr

essedinpa

tien

ts.

Srisu

rapa

non

tan

dJa

rusu

raisin

(199

8)

18–65

Opiatewithdr

awal

insomnia

6-da

yrand

omized

,do

uble-blind

trial.AMT

25–10

0mg/da

yvs.

lorazepa

m1–

4mg/da

y.N

=27

.

Eas

eof

gettingto

sleep

question

nairescores

ontheSEQ

were17

7.46

53.9

forAMT

and

184.56

85.4

forlorazepa

m,P

=0.80

.Eas

eof

awak

eningfrom

sleepon

theSEQ

was

132.86

47.9

forAMT

and16

7.66

38.4

forlorazepa

m,P

=0.04

7.

Non

eof

thepa

tien

tsrepo

rted

any

seriou

sAEsdu

ringthestudy

.Awak

eningfrom

sleepafter

AMT

was

moredifficult

than

afterlorazepa

m.

AMT

isas

effectiveas

lorazepa

mat

redu

cing

symptom

sof

insomnia

associated

withop

iate

withdr

awal

syndr

ome,

thou

ghit

may

beas

sociated

witha

hang

over

effect.


in vitro data indicate that cytochromes 2D6, 1A2, and3A are responsible for the formation of its metabolites(US FDA, 2007b).4. Results in Insomnia Disorder. No studies of

mirtazapine as a treatment of primary insomnia wereidentified, except for a case series (Dolev, 2011) con-ducted in perimenopausal women who suffered frominsomnia (N = 11) and who were not depressed by theHAM-D scale (Hamilton, 1960). In this study, thesubjects were given mirtazapine 15 mg/day for 2–4 weeks followed by treatment with prolonged-releasemelatonin 2 mg/day concurrent with the tapering ofmirtazapine over 1–3 months. Combination treatmentwith mirtazapine and melatonin during the taperingperiod reduced PSQI global scores from 14.45 6 1 atbaseline to 6.00 6 0.7 at endpoint. Sleep latency asmeasured by PSQI question 2 decreased from 52.73 614.04 minutes at baseline to 18.64 6 2.87 minutes atendpoint.5. Other Results. Five studies of mirtazapine as a

treatment of secondary insomnia were identified. Therewas one open-label study (N = 36) in patients withadvanced cancer and pain or other distressing symp-toms, including insomnia (Theobald et al., 2002); oneopen-label trial (N = 6) in patients diagnosed withmajordepressive disorder and poor sleep quality (Winokuret al., 2000); one randomized trial (N = 19) comparingmirtazapine to fluoxetine in patients diagnosed withmajor depressive disorder and insomnia (Winokuret al., 2003); one open-label study (N = 53) in patientswith cancer and comorbid MDD, anxiety disorders, oradjustment disorder (Cankurtaran et al., 2008); and oneopen-label study (N = 42) in patients with cancer andMDD (Kim et al., 2008). In these studies, mirtazapinewas generally effective at reducing symptoms of in-somnia; in the randomized trial, it was more effectivethan fluoxetine (Winokur et al., 2003).6. Conclusion. A summary of the effects of mirtaza-

pine on sleep architecture is presented in Table 2. Thereis weak evidence that mirtazapine is effective at re-ducing symptoms of insomnia disorder, based on onecase series (Dolev, 2011) and the available open-labelevidence of mirtazapine’s effectiveness in secondaryinsomnia.

C. Trazodone

1. Mechanism of Action. Trazodone’s effect as ahypnotic is attributable to its moderate antihistaminer-gic activity at the H1 receptor, its partial agonism at the5HT1A receptor (Odagaki et al., 2005), its antagonism ofthe 5HT1C and 5HT2 receptors, and its antagonism ofthe postsynaptic a1-adrenergic receptor (Schatzbergand Nemeroff, 2009; McCall, 2016). It also exerts rela-tively weak, although specific, reuptake inhibitioneffects at the 5-HT transporter (see Table 1 for asummary of trazodone’s main targets). Thus, trazodonehas amixed profile as both an agonist and an antagonist

of serotonin receptors. In rats, trazodone has beenshown to increase NREMS without affecting REMS(Lelkes et al., 1994).

2. Indications. Trazodone is FDA approved for thetreatment of depression. A survey revealed that trazodonewas the first-line choice of 78% or psychiatrists whenprescribing medications to treat SSRI-induced insomnia(Dording et al., 2002). As mentioned previously, in 2002,trazodone was the most commonly prescribed medicationfor insomnia, with 34% more prescriptions than the mostcommonly prescribed FDA-approved treatment (Walsh,2004). Clinical studies examining the hypnotic effects oftrazodone are detailed in Table 10.

3. Pharmacokinetics. Trazodone’s half-life is 7.0 61.2 after multiple oral administration and shows linearpharmacokinetics within the dosage range of 50–150 mg/day (Nilsen et al., 1993). Its absorption isirregular in fasting subjects, but it is improved if thedrug is taken after food. However, no differences areobserved in the total amount of trazodone absorbedwithand without food: its bioavailability values are 65 6 6%and 63.4%, respectively (Nilsen and Dale, 1992). Thedrug is primarily metabolized by the liver enzymeCYP3A4, and inhibition of this enzyme by other drugsleads to high blood levels of trazodone (Rotzinger et al.,1998). CYP3A4 mediates the metabolism of trazodone toits main active metabolite, m-chlorophenylpiperazine,which has 5-HT2C agonist and 5-HT2A antagonisticproperties (Rotzinger et al., 1998).

4. Results in Insomnia Disorder. One 2-week paral-lel group RCT (N = 306) in patients with primaryinsomnia was identified (Walsh et al., 1998). The studycompared treatment with trazodone 50 mg/day totreatment with zolpidem 10 mg/day and placebo aftera 1-week placebo lead-in period. During the first week,both drugs produced significantly shorter self-reportedsleep latency and longer self-reported sleep durationthan placebo. Sleep latency was significantly shorterwith zolpidem thanwith trazodone. Duringweek 2, onlythe zolpidem group maintained a significantly shortersleep latency than the placebo group, and sleep durationdid not vary significantly among groups.

5. Other Results. Two reviews on the use of trazo-done as a treatment of insomnia were identified (Jamesand Mendelson, 2004; Mendelson, 2005). Both reviewspredominantly analyzed studies of trazodone in pa-tients diagnosed with major depressive disorder. Al-though trazodone was shown to increase total sleeptime in patients with MDD (James and Mendelson,2004), there was limited evidence of its efficacy(Mendelson, 2005). The high rate of discontinuationdue to adverse events, which included sedation, dizzi-ness, and psychomotor impairment, make the risk-benefit ratio of trazodone therapy for insomnia un-certain (Mendelson, 2005). Furthermore, there is a riskof priapism in 1 out of 6000 patients treated withtrazodone (James and Mendelson, 2004).

222 Atkin et al.

TABLE

9Sum

maryof

stud

iesas

sessingtheeffectsof

mirtaza

pine

(MRT)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clus

ion

Aslan

etal.

(200

2)18

–30

You

nghea

lthyvo

lunteers

RCT

withacuteinjectionof

MRT(30mg)

vs.p

lacebo

.N

=20

.

MRT

increa

sedstag

eN3,

sleep

efficien

cy,didnot

alterREM

sleep

andde

crea

sedthenumbe

rof

awak

enings

andtheirdu

ration

during

sleep.

Not

analyz

ed.

MRTis

effectivein

indu

cing

NREM

slee

pwithou

taffectingREM

sleepin

healthysu

bjects.

Can

kurtaran

etal.(20

08)

18–65

Can

cerwithmajor

depr

essive

disord

er,

anxietydisord

ers,

orad

justmen

tdisord

er

6-wkop

en-lab

eltrial.MRT

5–30

mg/da

yvs.

imipramine5–

100mg/

dayvs.un

trea

tedcontrol

grou

pthat

refuseddr

ugtherap

y.N

=53

.

Percent

ofpa

tien

tsrepo

rtingnightly

difficulty

fallingas

leep

inMRT

grou

pde

crea

sedfrom

65at

baseline

to15

aten

dpoint

vs.ade

crea

sefrom

53.8

atba

seline

inim

ipramine

grou

pto

30.8

aten

dpoint

vs.a

decrea

sefrom

50at

baseline

incontrolgrou

pto

30at

endp

oint.

Not

analyz

ed.

MRTis

effectiveat

redu

cing

symptom

sof

insomniain

canc

erpa

tien

ts,an

dmoreeffectivethan

imipramine.

Dolev

(201

1)45

–52

Perim

enop

ausa

lwom

enwithinsomnia

whodid

not

suffer

from

depr

ession

byHAM-D

Cas

eseries.MRT

15mg/

dayfor2-4wkfollow

edby

trea

tmen

twith2mg

prolon

ged-releas

emelaton

inwithtape

ring

ofMRT

for1–

3mo.

N=

11.

Com

bina

tion

trea

tmen

twithMRT

andmelaton

indu

ringMRT

tape

ring

period

redu

cedPSQI

glob

alscores

from

14.456

1at

baseline

to6.00

60.7at

endp

oint.

SOLas

mea

suredby

PSQIqu

estion

2(m

inute)

decrea

sedfrom

52.736

14.04at

baseline

to18

.646

2.87

aten

dpoint.

NoAEswererepo

rted

.MRTfollow

edby

prolon

ged-

releas

emelaton

inad

d-on

trea

tmen

tfollow

edby

melaton

inmon

othe

rapy

iseffectiveat

redu

cing

symptom

sof

insomniain

perimen

opau

salwom

en.

Kim

etal.(200

8)22

–79

Can

cerpa

tien

tswith

depr

ession

4-wkop

en-lab

eltrial.MRT

15–45

mg/da

y.N

=42

.Amou

ntof

sleep(hou

rs)increa

sed

from

3.66

1.9at

baseline

to6.86

2.5at

endp

oint,P

,0.00

1.Eas

eof

gettingto

sleepsu

bscale

ofthe

Cho

nnam

Nationa

lUnive

rsity

Hospital-Leeds

Sleep

Eva

luation

Que

stionn

aire

decrea

sedfrom

4.26

1.0at

baseline

to2.46

1.0at

endp

oint,P

,0.00

1.

Fou

rpa

tien

tsdiscon

tinued

MRT

dueto

side

effects

(Twodu

eto

seda

tion

andon

eea

chfor

general

wea

knessor

cons

tipa

tion

).

MRTis

effectiveat

redu

cing

symptom

sof

insomniain

canc

erpa

tien

ts.

Theoba

ldet

al.

(200

2)40

–83

Adv

ancedcancerpa

tien

tswithpa

inan

dothe

rdistressingsymptom

s

Ope

n-labe

lcrossove

rstud

yof

MRT

15/30mg/da

y.N

=36

.

The

rewereno

sign

ifican

tdifferen

ces

onNRSscales

mea

suring

insomnia.

How

ever,therewas

atren

dtoward

impr

oved

sleep.

Only

onepa

tien

twithdr

ewdu

eto

MRT

side

effects.

MRT

may

beeffectiveat

redu

cing

symptom

sof

insomnia

incancer

patien

ts.

Winok

uret

al.

(200

0)18

–65

Major

depr

essive

disord

erwithpo

orsleepqu

ality

2-wkop

en-lab

elstud

y.MRT

15–30

mg/da

y.N

=6.

SOL

impr

oved

,P

=0.00

9.TST

impr

oved

,P=0.00

4.SE

impr

oved

,P=0.00

03.M

RTdidno

tsign

ificantly

affect

REM

sleeppa

rameters.

Fourof

sixsubjects

reported

daytim

esomnolencedu

ring

week

1,though

thecomplaints

resolved

byweek2.

MRTis

effectiveat

redu

cing

symptom

sof

insomnia.

Winok

uret

al.

(200

3)18

–45

Major

depr

essive

disord

erwithinsomnia

8-wkrand

omized

trial.

MRT

15–45

mg/da

yvs.

fluo

xetine

20–40

mg/da

y.N

=19

.

MeanSO

L(m

inute)

bypolysomno

grap

hydecreasedfrom

34.3

624

.0at

baselin

eto

10.9

69.6at

Week9in

MRTgrou

p,P,

0.05

vs.3

8.66

32.2

atba

selin

eto

43.3

628

.4at

Week8in

fluoxetine

grou

p.Total

sleeptime(m

inute)

increasedfrom

327.96

81.8

atba

selin

eto

428.16

73.6

atWeek8in

MRTgrou

p,P,

0.05

vs.3

17.4

668

.8at

baselin

eto

325.16

116.4in

fluoxetinegrou

p.

Not

analyz

ed.

MRTis

effectiveat

redu

cing

symptom

sof

insomnia,

andsu

perior

tofluo

xetine

.


TABLE

10Sum

maryof

stud

iesas

sessingtheeffectsof

traz

odon

e(TRZ)

onsleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Cam

argo

set

al.

(201

4)60

+Alzhe

imer’sdiseas

e2-wkRCT.TRZ50

mg/da

yvs.placeb

o.N

=30

.Actigraph

y:TRZsu

bjects

slep

t42

.5min

morethan

placeb

osu

bjects

andpe

rcen

tsleepincrea

sed8.5%

.Noeffect

oncogn

itionor

WASO

ornu

mbe

rof

awak

enings

AEstran

sien

tan

dmild.

Trazodo

nemay

beeffectiveat

redu

cing

symptom

sof

insomniain

olde

rad

ults

withAlzheimer’sdiseas

e.

Cunningh

amet

al.(19

94)

18+

Major

depr

ession

6-wkRCTof

traz

odon

evs.

venlafax

inevs.placeb

o.96

resp

onde

rscontinue

din

a1-yr

doub

le-blind

continua

tion

phas

e.Ave

rage

doses:

156–

160mg/da

yve

nlafax

ine

and29

4–30

0mg/da

yTRZ.N

=22

5.

TRZpr

oduc

edmoreim

prov

emen

ton

thesleepdistur

banc

efactor

ofthe

HAM-D

,bu

tve

nlafax

inemore

effectivein

cogn

itivedistur

banc

ean

dretard

ationfactorsof

theHAM-

D.

Significantly

morepa

tien

tsdiscon

tinued

TRZdu

eto

dizzinessthan

patien

tstaking

placeb

oor

venlafax

ine.

Significantly

morepa

tien

tsdiscon

tinu

edve

nlafaxinedu

eto

nau

sea.

TRZis

effectiveat

redu

cing

symptom

sof

insomnia

inpa

tien

tswithMDD.

Fried

man

net

al.

(200

8)16

–65

DSM-IV

curren

talcoho

lde

pend

ence

andsleep

disturban

ce

12-w

kRCT.TRZ50

–

150mg/da

yvs.placeb

o.N

=17

3.

TRZgrou

pexperien

cedless

improvem

ent

inproportion

ofda

ysab

stinen

tdu

ring

administrationof

medication,

andan

increase

inthenu

mberof

drinks

per

drinking

dayon

cessationofstud

y.TRZ

improved

sleepqu

ality(PSQ

Imean

chan

ge23.02

[23.38

,22.67

]),bu

tafter

cessationsleepqu

alityequa

lized

with

placebo.

TRZgrou

prepo

rted

moredr

ymou

th.

Althou

ghTRZredu

ced

symptom

sof

insomnia,

itmay

impe

deim

prov

emen

tsin

alcoho

lism

during

detoxification

andlead

toincrea

seddr

inkingwhen

stop

ped.

Haffm

ansan

dVos

(199

9)mea

n:44

Previou

sseve

remajor

depr

ession

;cu

rren

tinsomniasecond

ary

tobrofarom

ine

trea

tmen

t

Crossov

erRCT.T

RZ50

mg/

dayas

adjunct

tobrofarom

ine15

0–25

0mg/

day.

N=7.

TRZdidno

tim

prov

eSOL,total

sleep

time,

ortimeaw

ake.

TRZredu

ced

thenumbe

rof

awak

enings

(P=

0.01

9)an

dincrea

sedstag

eIV

sleep

(P=0.08

8).

WhiletakingTRZ,on

epa

tien

trepo

rted

cons

tipa

tion

and

naus

ea,o

nepa

tien

trepo

rted

vertigo,

drymou

th,a

nd

palpitations,

andon

epa

tien

tha

dting

ling

feelings

inch

inan

dmod

eratehe

artbur

n.

TRZmay

not

beeffectiveat

redu

cing

symptom

sof

insomniasecond

aryto

trea

tmen

twithstim

ulating

antide

pressa

nts,

butmay

increa

seslow

-wav

esleep.

James

and

Men

delson

(200

4)

Varied.

Varied.

Rev

iew.

TRZincrea

sestotalsleeptimein

patien

tswithMDD,tho

ughthere

arefew

data

tosu

pportitsus

ein

non-de

pressedpa

tien

ts.

The

reis

ano

tablerisk

ofpriapism

in1ou

tof

6000

patien

tstrea

tedwith

TRZ.

The

reis

also

arisk

oforthostatichy

potens

ionan

dtheindu

ctionof

cardiac

arrhythm

iasin

patien

tswith

preexistingcardiacdisease.

TRZha

smoreside

effectsthan

conv

ention

alhy

pnotics,

mak

ingitsrisk

-ben

efit

ratio

uncertain.

Karam

-Hag

ean

dBrower

(200

3)seeGab

apen

tinsection

Kay

nak

etal.

(200

4)20

–50

Insomnia

seconda

ryto

trea

tmen

tw/SSRI,

DSM-IV

depr

ession

2-wkcrossove

rRCTw/

1-wkwas

hou

t.TRZ

100mg/da

y+SSRIs

vs.

placeb

o+SSRIs.N

=12

.

TRZsign

ificantly

increasedtotals

leep

time,percen

tage

ofstage3an

d4sleep,

SE,sleep

continuity

anddecreased

numberof

awak

enings.A

tweek3,

completingboth

TRZan

dplacebo

treatm

ents

w/w

asho

ut,m

eanglobal

PSQ

Iscores

inboth

grou

psredu

ced

from

156

2.5to

56

1.6.

Total

polysomno

grap

hicsleeptime(m

inute)

increasedfrom

382.17

658

to42

86

39on

last

TRZnigh

t,P,

0.05

.SOL

notsign

ificantly

improved.

TRZpe

riod

associated

w/o

nesu

bjectrepo

rtingmild

acid

indigestionan

dtw

orepo

rting

mild

daytim

eseda

tion

.

TRZmay

beeffectiveat

redu

cingsymptom

sof

SSRI-

indu

cedinsomnia.

(con

tinued

)

224 Atkin et al.

TABLE

10—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

LeBon

etal.

(200

3)18

–65

Alcoh

olde

pende

nce

withph

ysiologic

depe

nde

nce

byDSM-

IV;alcoho

l-indu

ced

sleepdisord

ers,

insomnia

type

(DSM-

IV)

4-wkRCT.TRZ50

mg/da

yvs.placeb

o.N

=16

.SE

was

increa

sedin

TRZgrou

p.No

bene

fitin

placeb

ogrou

p.HAM-D

andCGIwerealso

better

inTRZ

grou

p.

Mostfreq

uen

tAEsin

theTRZ

grou

pwerehan

gove

rsan

ddizziness.

Doseredu

ction

from

200to

150mg/da

yredu

cedtheseAEs.

Inplaceb

ogrou

p:AEsinclude

dhe

adache

s,ha

ngov

er,an

dsk

inirritation

.

TRZmay

beeffectiveat

redu

cing

symptom

sof

insomnia.

Men

delson

(200

5)Varied.

Varied.

Rev

iew

of18

stud

ies.

Lim

ited

eviden

ceof

efficacy

ofTRZ,

man

ytrials

weresm

allan

dwere

cond

uctedin

depr

essedpa

tien

ts.

Highrate

ofdiscon

tinu

ation

dueto

side

effectsinclud

ing

seda

tion

,dizziness,

and

psycho

motor

impa

irmen

t.Thisraises

conc

erns

abou

ttheuse

ofTRZin

theelde

rly.

TRZrisk

-ben

efit

ratioin

insomniaremains

uncertain.

Mou

retet

al.

(198

8)35

–60

depr

essedin-patients

withaMADRS

score.20

Ope

n-labe

lstud

ywithTRZ

(400

–60

0mg/da

y)for

5wk.

N=10

.

TRZde

crea

sedlatenc

yto

sleepon

set

andintras

leep

awak

enings,

increa

sedTST

anddidnot

affect

REM

sleeptime.

Anincrea

sein

REM

sleeplatenc

ywas

foun

don

lyat

theen

dof

the5-wktrial.

Nau

sea,

dizziness.

TRZis

effectiveat

redu

cing

symptom

sof

insomnia

inde

pressedpa

tien

ts.

Nierenbe

rget

al.

(199

4)mea

n:41.9

S.D

.:10

Antidep

ressan

t-as

sociated

insomnia

inpa

tien

tstrea

ted

withfluo

xetine

orbu

prop

ion

Crossov

erRCT.T

RZ50

mg/

dayvs.placeb

o.Mea

nleng

thof

trea

tmen

t:6.5da

ysforTRZvs.

4.6da

ysforplaceb

o.N

=17

.

67%

repo

rted

impr

ovem

entwithTRZ

vs.13

%withplaceb

o.Im

prov

emen

twithTRZan

dnot

placeb

oon

PSQI

andYale-New

Hav

enscores.

Day

timeseda

tion

occu

rred

inon

epa

tien

t.Priap

ism

didnot

occu

r,bu

ton

epa

tien

tde

velope

dapr

olon

ged

erection

,pr

omptingado

sede

crea

se.

TRZmay

beeffectiveat

redu

cing

symptom

sof

insomnia.

Sch

arfan

dSachais(199

0)Dep

ressed

patien

tswith

sleepdisturban

ces

8-wksing

le-blind

stud

ywithTRZ15

0–40

0mg/

day.

N=6.

After

5wk,

TRD

impr

oved

sleep

efficien

cy(from

80.6

612

.3%

to91

.96

4.9%

),increa

sedTST

(from

387.16

59.2

to44

1.36

23.7

min),

prolon

gedREM

sleeplatenc

ybu

tdidnot

affect

theam

ount

ofREM

sleep.

TRZen

hanc

edsleep-related

penile

tumescenc

e.

Not

analyz

ed.

TRZaffectsREM

sleepin

youngmen

andredu

ced

awak

enings

andmov

emen

t/arou

sals

prob

ably

dueto

its

seda

ting

prop

erties.

Stein

etal.

(201

2)mea

n:38

.2S.D

.:8.6

Methad

one

maintenan

cetrea

tmen

tof

opioid

depe

nde

nce

6-moRCT.T

RZ50

–15

0mg/

dayvs.placeb

o.N

=13

7.Placebo

subjects

repo

rted

sign

ifican

tly

high

ersleepqu

alityrating

sthan

TRZsu

bjects,P

=0.04

.Polysom

nograp

hy:totalsleeptime

was

notsign

ifican

tlyim

prov

edin

TRZsu

bjects,P

=0.18

.

Betweenba

seline

and1mo,

TRZgrou

psign

ifican

tly

morelike

lyto

repo

rtincrea

sedthirst

ordr

ymou

th,P=0.00

1,an

dde

crea

sedap

petite,P

=0.04

.

Trazodo

neis

not

effectiveat

redu

cing

symptom

sof

insomniain

patien

tson

methad

onemaintenan

cetrea

tmen

twithsleep

distur

banc

e.

Walsh

etal.

(199

8)21

–65

Primaryinsomnia

byDSM-IIIR

2-wkpa

rallel-group

compa

risonRCT.TRZ

50mg/da

yvs.zolpidem

10mg/da

yvs.placeb

owith1-wkplaceb

olead

-in.N

=30

6.

Dur

ingfirstweek,

both

drug

spr

oduc

edsign

ifican

tlysh

orterself-

repo

rted

SOL(SSL)an

dlong

erself-

repo

rted

sleepdu

ration

(SSD)than

placeb

o.SSLwas

sign

ifican

tly

shorterwithzolpidem

than

with

TRZ.

Dur

ingWeek2,

only

the

zolpidem

grou

pmaintaine

da

sign

ifican

tlysh

orterSOL

than

the

placeb

ogrou

p,an

dSSD

didnot

vary

sign

ifican

tlyam

onggrou

ps.

Treatmen

t-em

ergent

AEs

reported

by65

.4%

ofplacebo

patien

ts,7

6.5%

ofzolpidem

patien

ts,a

nd75

%of

TRZ

patien

ts.H

eada

cheoccurred,

respectively,in19

%,2

4%,a

nd30

%of

participan

ts.

Somno

lenceoccurred,

respectively,in8%

,16%

,and

23%

ofpa

rticipan

ts.T

reatmen

tgene

rally

well-tolerated.

TRZmay

beless

effectivethan

zolpidem

atdo

sesstud

iedat

redu

cing

symptom

sof

insomnia.

(con

tinued

)


Nine RCTs on the use of trazodone in the treatment ofinsomnia secondary to other conditions were identified,of which three were conducted in patients with in-somnia secondary to treatment with antidepressants(Nierenberg et al., 1994; Haffmans and Vos, 1999;Kaynak et al., 2004). One crossover RCT (N = 17) oftrazodone 50 mg/day versus placebo in antidepressant-associated insomnia secondary to treatment with flu-oxetine or bupropion (Nierenberg et al., 1994) and one2-week crossover RCT (N = 12) of trazodone 100 mg/dayversus placebo in patients with insomnia secondary totreatment with SSRIs (Kaynak et al., 2004) foundtrazodone effective, with significantly increased totalsleep time, sleep efficiency, sleep continuity, and in-creased stage 3 and stage 4 sleep in the second trial.However, one smaller RCT (N = 7) of trazodone 50 mg/day in antidepressant-associated insomnia secondary totreatment with brofaromine (Haffmans and Vos, 1999)found that trazodone did not improve sleep latency,total sleep time, or time awake versus placebo, althoughit increased SWS. These results suggest that trazodonemay be effective in cases of insomnia induced by SSRIsor bupropion, but not brofaromine, an antidepressantthat was never brought to market.

A 6-week study of trazodone versus venlafaxineversus placebo in patients diagnosed with major de-pression was also identified (Cunningham et al., 1994):in this study, trazodone was more effective for improv-ing sleep disturbance on the HAM-D, but venlafaxinewas better at relieving cognitive disturbance and re-tardation. Trazodone caused more dizziness whilevenlafaxine caused more nausea.

Three studies of trazodone in the context of addictionwere identified. One 4-week RCT (N = 16) of trazodone50 mg/day versus placebo in patients with alcohol-induced insomnia and alcohol dependence (Le Bonet al., 2003) found that trazodone increased sleepefficiency. However, caution is warranted because alarge 12-week RCT (N = 173) of trazodone 50–150 mg/day versus placebo in patients with alcohol dependenceand sleep disturbances (Friedmann et al., 2008) foundthough trazodone reduced symptoms of insomnia, andthe trazodone group experienced less improvement inthe proportion of days abstinent during detoxificationwhen receiving medication; furthermore, the trazodonegroup had an increase in the number of drinks perdrinking day upon cessation of the study. A 6-monthRCT (N = 137) of trazodone 50–150 mg/day duringmethadone maintenance treatment of opioid depen-dence (Stein et al., 2012) was negative, with placebo-treated subjects reporting significantly higher sleepquality ratings than trazodone-treated subjects.

Finally, a 2-week RCT (N = 30) of trazodone 50 mg/dayin patients with Alzheimer’s disease found thattrazodone-treated subjects slept significantly longer thanplacebo-treated subjects, although the drug did not have adetectable effect on cognition (Camargos et al., 2014).

TABLE

10—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Wareet

al.

(199

4)20

–34

Hea

lthymales

Crossov

erRCT.TRZ

100–

200mg/da

yvs.

nefaz

odon

e20

0–40

0mg/

day,

vs.bu

spiron

e10

–20

mg/da

y,an

dvs.

placeb

o.N

=12

.

TRZan

dbu

spiron

eredu

cedREM

sleepam

ount

andincrea

sedREM

sleeplatenc

ywhe

reas

nefaz

odon

een

hanc

edREM

sleepwitho

utaffectingREM

sleeplatenc

y.TRZ

The

drug

sdidno

taffect

NREM

sleep.

TRZredu

cedthenu

mbe

rof

awak

enings

andthenu

mbe

rof

mov

emen

t/arou

sals

compa

redwith

placeb

o

Not

analyz

ed.

TRZsu

ppress

REM

slee

pan

dpr

olon

gspe

nile

tumescenc

edu

ringslee

p.

Yam

aderaet

al.

(199

8)21

–28

Hea

lthymales

Single-blindstudy

.TRZ

100mg/da

yvs.

imipramine40

mg/da

yvs.placeb

o.N

=8.

TRZincrea

sedstag

eN3an

dde

crea

sed

stag

eN1-N2vs.placeb

o,an

dun

like

lyim

ipramine,

didnot

alter

REM

slee

p.

Not

analyz

ed.

TRZincrea

sedNREM

slee

pwitho

utaffectingREM

sleep

inyo

unghea

lthymales.

226 Atkin et al.

6. Conclusion. A summary of the effects of trazodoneon sleep architecture is presented in Table 2. There isgood evidence that trazodone is effective at reducingsymptoms of insomnia in patients with SSRI-inducedinsomnia based on two RCTs (Nierenberg et al., 1994;Kaynak et al., 2004). Trazodone use is discouraged ininsomnia associated with opioid dependence or alcohol-ism based on one negative RCT in patients on metha-donemaintenance treatment (Stein et al., 2012) and thesafety concerns in one RCT conducted in patients withalcoholism (Friedmann et al., 2008).

D. Low-Dose Doxepin (,6 mg/day)

1. Mechanism of Action. Doxepin is a tricyclicantidepressant with significant antihistaminic effects.Doxepin is themost potent antihistamine of the tricyclicantidepressants, with four times the potency of ami-triptyline and 800 times the potency of diphenhydra-mine at the H1 receptor (Richelson, 1979; Gillman,2007). At standard antidepressant doses, .75 mg/day,doxepin inhibits the reuptake of serotonin and norepi-nephrine and antagonizes cholinergic, histaminergic,and a-adrenergic activity. As a hypnotic, doxepin isused at low doses; at doses ,10 mg/day, it theoreticallyaffects only the histamine receptor, with no meaningfuleffects on the noradrenergic and serotonergic systems(McCall, 2016) (see Table 1).2. Indications. Low-dose doxepin , under the brand

name Silenor (Pernix Therapeutics, Morristown, NJ),is FDA approved for the treatment of insomniacharacterized by difficulties with sleep maintenanceto a maximum dose of 6 mg/day (US FDA, 2010b).Doxepin is also approved as an antidepressant inthe treatment of “psychoneurotic patients with de-pression and/or anxiety.” Clinical studies examiningthe hypnotic effects of low-dose doxepin are detailed inTable 11.3. Pharmacokinetics. Low-dose doxepin has a ter-

minal half-life of 15.3 hours, whereas the half-life ofnordoxepin, Median to peak concentration (Tmax) ofdoxepin 6 mg occurs 3.5 hours after oral administrationto healthy fasted subjects; Tmax is delayed by approxi-mately 3 hours if the drug is taken with a high-fat meal,whereas AUC is increased by 41% and Cmax by 15% (USFDA, 2010b). For this reason, it is recommended thatdoxepin be taken without food, to minimize the risk ofnext day effects. The major liver enzymes responsiblefor the metabolism of doxepin are CYP2C19 andCYP2D6, whereas CYP1A2 and CYP2C9 are involvedto a lesser extent. The drug is 80% bound to plasmaproteins. Notably, doxepin interacts with cimetidine(causes a twofold increase in doxepin Cmax and AUC)and sertraline (causes AUC to be increased 21% andCmax to be increased 32%) (US FDA, 2010b).4. Results in Insomnia Disorder. One systematic

review (Yeung et al., 2015), five published RCTs (Rothet al., 2007; Scharf et al., 2008a; Krystal et al., 2011,

2010; Lankford et al., 2012), and one unpublished RCT(Takeda Global Research & Development Center Inc.,2008) of low-dose doxepin as a treatment of primaryinsomnia were identified. The systematic review in-cluded two studies of doxepin at antidepressant doses(25–300 mg/day) that are excluded in this review. Theauthors did not perform meta-analysis of pooled resultsdue to heterogeneity but confirmed that low-dosedoxepin had a small to medium effect size versusplacebo for sleep maintenance and sleep duration, butwas ineffective at improving the time to sleep onset. Thefindings in the individual RCTs cited above generallycame to similar conclusions as the recent systematicreview, although some RCTs used subjective measure-ments and others used polysomnographic measurements.

The unpublished clinical trial is a double-dummystudy of ramelteon + low-dose doxepin versus each drugas monotherapy versus placebo (Takeda Global Re-search & Development Center Inc., 2008). It found thatramelteon + low-dose doxepin was significantly moreeffective than ramelteon + placebo by polysomnography-measured wake time after sleep onset and total sleeptime, as well as subjective wake time after sleep onset.

5. Other Results. A single night RCT of low-dosedoxepin in healthy volunteers was also identified (Rothet al., 2010). In this trial, the investigators attempted toinduce transient insomnia using the first-night effect aswell as a 3-hour phase advance. Low-dose doxepin waseffective at reducing latency to sleep and increasingtotal sleep time.

6. Conclusion. A summary of the effects of low-dosedoxepin on sleep architecture is presented in Table 2.There is strong evidence that low-dose doxepin iseffective at reducing symptoms of primary insomniabased on one systematic review (Yeung et al., 2015), fivepublished RCTs (Roth et al., 2007; Scharf et al., 2008a;Krystal et al., 2011, 2010; Lankford et al., 2012), andone unpublished RCT (Takeda Global Research & De-velopment Center Inc., 2008). Low-dose doxepin exertsa strong on improving sleep maintenance.

VII. Anticonvulsant Drugs

A. Gabapentin

1. Mechanism of Action. Gabapentin is an anticon-vulsant drug that binds to the a2d subunit of voltage-sensitive calcium channels (Gee et al., 1996) (Table 1). Itcrosses several lipid membrane barriers; in vitro, it hasbeen shown to modulate the activity of the GABAsynthesizing enzyme, glutamic acid decarboxylase,and the glutamate synthesizing enzyme, branched-chain amino acid transaminase (Taylor, 1997). Itsmodulation of the GABAergic and glutamatergic sys-tems probably underlies its effect as a hypnotic andanxiolytic. Gabapentin is known to increase SWSwithout affecting other polygraphic variables and with-out causing increased drowsiness during the day


TABLE

11Sum

maryof

stud

iesas

sessingtheeffectsof

low-dosedo

xepine

(DXP)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Krystal

etal.

(201

0)65

+Primaryinsomnia

byDSM-IV

12-w

kRCT.DXP

1mg/da

yvs.

3mg/da

yvs.placeb

o.N

=24

0.

LPSwas

not

sign

ifican

tlydifferen

tfrom

placeb

oforan

ydo

seof

DXP.

How

ever,WASO

was

sign

ifican

tly

redu

cedat

alltimepo

ints

inthe

DXP

3mg/da

ygrou

p(P

,0.00

1)an

don

night1(P

,0.01

)an

dnight

85(P

,0.05

),bu

tnot

nigh

t29

intheDXP1mg/da

ygrou

p.TST

was

increa

sedsign

ifican

tlyin

theDXP

3mg/da

ygrou

pat

alltimepo

ints

andin

theDXP1mg/da

ygrou

pat

night1(P

,0.05

)an

dnight85

(P,

0.05

)bu

tnot

night29

.

Rates

oftrea

tmen

t-em

erge

ntAEs

werelower

intheDXP

grou

psthan

theplaceb

ogrou

p:52

%of

placeb

osu

bjects

repo

rted

anAE

compa

red

withDXP1mg/da

y(40%

)an

dDXP

3mg/da

y(38%

).Less

discon

tinu

ationwithDXP

aswell:

placeb

odiscon

tinu

ationwas

14%,

DXP

1mg/da

ywas

9%,DXP3mg/

daywas

10%.Noev

iden

ceof

nex

t-da

yseda

tion

.

Low

-doseDXP

iseffective

atredu

cingsymptom

sof

insomnia.

Krystal

etal.

(201

1)18

–64

Primaryinsomniaby

DSM-IV-TR

35-day

RCT

follow

edby

two

nightsof

sing

le-blind

placeb

otrea

tmen

tto

assess

discon

tinu

ationeffects.

DXP

3mg/da

yvs.6mg/da

yvs.

placeb

o.N

=22

1.

Bypo

lysomnog

raph

y:LPSwas

only

impr

oved

relative

toplaceb

oin

both

DXP3an

d6mg/da

yon

night1,

P,

0.00

01,an

dno

tim

prov

edon

nigh

t15

or29

.TST

was

sign

ifican

tly

impr

oved

forbo

thdo

sesan

dforall

timepo

ints

except

night

15in

the

3mg/da

ygrou

p.WASO

was

sign

ifican

tlyim

prov

edat

alltime

points

andin

both

dosa

gegrou

ps.

Rates

ofdiscon

tinu

ationweresimila

rbe

tweentrea

tmen

tarms:

placeb

o=

12%,D

XP3mg/da

y=12

%,D

XP

6mg/da

y=11

%.N

oclinically

meaning

fulchan

gesin

mea

nlaboratory

values,E

CGs,

body

weigh

t,or

vitalsign

s.

Low

-doseDXP

iseffective

atredu

cingsymptom

sof

insomnia.

DXP

seem

spa

rticularly

effectiveat

maintaining

sleep.

Lan

kfordet

al.

(201

2)65

+Primaryinsomniaby

DSM-IV-TR

4-wkRCT.DXP6mg/da

yvs.

placeb

o.N

=25

5.Sub

jectiveTST

(minute)

increa

sed

from

283.16

50.0

to34

6.16

66.4

atwee

k4in

theDXP

grou

pvs.an

increa

sefrom

293.56

49.1

to33

6.4

664

.7at

week4in

theplaceb

ogrou

p,P

,0.01

(DXP

sepa

rated

from

placeb

oon

this

mea

sure

byweek1).Sub

jectiveWASO

was

redu

cedrelative

toplaceb

oat

week

1(P

,0.00

01)an

dwee

k4

(P,

0.01

).

Rates

ofAEsweresimila

rbetw

een

grou

ps:2

7%forplaceboan

d31

%for

DXP6mg/da

y.Rates

ofdiscon

tinu

ationwerelower

forDXP:

placebo=10

%vs.D

XP6mg/da

y=5%

.Nochan

gesin

laboratory

values,

ECGs,body

weigh

t,ne

urologic

exam

inations,o

rvitalsign

s.

Low

-doseDXP

iseffective

atredu

cingsymptom

sof

insomnia.

NCT#0

0755

495

seeRam

elteon

section

Rothet

al.(20

07)

18–64

Chronicpr

imary

insomniaby

DSM-IV

Fou

r-grou

pcrossove

rRCTwith

2po

lysomno

grap

hic

assessmen

tnightspe

rtrea

tmen

t.DXP1mg/da

yvs.

3mg/da

yvs.6mg/da

yvs.

placeb

o.N

=67

.

For

themeasuremen

tof

LPS

(polysom

nograp

hy),no

neof

the

treatm

ents

werestatistically

better

than

placeboby

onean

alysis;a

statisticalre-an

alysispo

stho

cfoun

dP

=0.01

39forDXP6mg.Allthreedo

ses

improved

totalsleeptimerelative

toplacebo:P=0.00

05forDXP1mg/da

y,P,

0.00

01forDXP3mg/da

y,P,

0.00

01forDXP6mg/da

y.

AEsin

theDXP

grou

psoccu

rred

ata

similar

rate

ofthosein

theplaceb

ogrou

pan

ddidnot

appe

arto

bedo

se-

related.

Hea

dach

ean

dsomno

lenc

ewerethemostcommon

AEs.

Low

-doseDXP

iseffective

inthetrea

tmen

tof

insomnia.

Alldo

sesof

DXP

sign

ifican

tly

impr

oved

SE

duringthe

entire

nigh

t,ea

chon

eP,

0.05

.Only

DXP3mg/

dayan

dDXP

6mg/da

ysign

ifican

tlyim

prov

edwak

etimedu

ring

sleep.

Rothet

al.(20

10)

25–55

Hea

lthypa

rticipan

tsrequ

ired

tohav

eno

history

ofinsomnia

andnormal

slee

ppa

tterns

during

last

3mo.

Transien

tinsomnia

was

indu

ced

inpa

rticipan

ts.

OnenightRCT.DXP

6mg/da

yvs.placeb

o.N

=56

5.Bypo

lysomnog

raph

y:LPSwas

47.7

659

.5min

intheplaceb

ogrou

pan

d31

.86

44.0

min

intheDXP

grou

p,P

,0.00

01.TST

was

increa

sed

51.1

min

intheDXP

grou

prelative

totheplaceb

ogrou

p,P

,0.00

01.

Incide

nceof

AEswas

similar

toplaceb

o.Onon

emea

sure

ofne

xt-

dayresidu

aleffects(the

Digit

Sym

bolSub

stitutionTest)

there

was

nodifferen

cebe

tweenDXPan

dplaceb

o.How

ever,DXPresu

lted

instatisticallysign

ifican

tworsening

ontw

oothe

rscales,theSym

bol

Cop

yingTestan

dtheVisual

Analog

Scale

forsleepine

ss.

DXPis

effectiveat

redu

cing

symptom

sof

insomnia.

(con

tinued

)

228 Atkin et al.

(Foldvary-Schaefer et al., 2002). In mice, gabapentinalleviates sleep disturbances induced by a neuropathicpain-like condition (Takemura et al., 2011).

2. Indications. Gabapentin is FDA-approved for themanagement of postherpetic neuralgia in adults (USFDA, 2014c). It is FDA approved as adjunctive treat-ment of partial seizures with and without secondarygeneralization in patients over 12 years old withepilepsy and as adjunctive treatment of partial seizuresin patients aged 3–12. Clinical studies examining thehypnotic effects of gabapentin are detailed in Table 12.

3. Pharmacokinetics. The bioavailability of gaba-pentin is inversely proportional to its daily dose: asdosage increases, bioavailability decreases. The bio-availability of gabapentin is 60%, 47%, 34%, 33%, and27% following oral administration of 900, 1200, 2400,3600, and 4800 mg/day of the drug given in threedivided doses (US FDA, 2014c). Less than 3% ofgabapentin is bound to plasma protein, and the drugis not appreciably metabolized in humans. Its elimina-tion half-life is 5–7 hours and is unaltered by dose orfollowing multiple dosing. Taking the drug with foodhas a small effect on its pharmacokinetics, increasingAUC and Cmax by 14% each.

4. Results in Insomnia Disorder. One open-labeltrial conducted in patients with primary insomnia wasidentified (Lo et al., 2010). This study (N = 18; meandose of gabapentin 540 mg/day, range 200–900 mg/day)found polysomnographic evidence of increased sleepefficiency (80.00%–87.17%, P , 0.05) and SWS(10.47%–17.68%, P , 0.005) and decreased wake timeafter sleep onset (16.45%–7.84%, P , 0.05) (Lo et al.,2010). However, gabapentin did not significantly im-prove sleep onset latency (17.58–14.58 minutes, notsignificant).

5. Other Results. Five other studies of gabapentinwere identified. Two of the four studies were RCTs: onewas conducted in patients diagnosed with alcohol de-pendence and comorbid insomnia (Brower et al., 2008)and the other was a single-dose study conducted inpatients with “occasional disturbed sleep” (Rosenberget al., 2014). One open-label comparison study ofgabapentin versus trazodone conducted in patientswithalcohol dependence and “persistent insomnia” (Karam-Hage and Brower, 2003) and an open-label studyconducted in children suffering from refractory in-somnia comorbid to neurodevelopmental or neuro-psychiatric disorders (Robinson and Malow, 2013)were also identified. Finally, one study in healthysubjects was identified (Foldvary-Schaefer et al.,2002).

In the RCT conducted in patients with alcohol de-pendence and comorbid insomnia (N = 21; gabapentin1500 mg/day), treatment group did not predict changesin the Sleep Problems Questionnaire score (Broweret al., 2008). However, gabapentin treatment signifi-cantly reduced the risk of relapse to heavy drinking: at

TABLE

11—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Sch

arfet

al.

(200

8b)

65+

Primaryinsomnia

byDSM-IV

Fou

r-pe

riod

crossove

rRCT.

DXP

1vs.3vs.6mg/da

yvs.

placeb

o.N

=76

.

LPSwas

not

sign

ifican

tlydifferen

tfrom

placeb

oforan

ydo

seof

DXP.

How

ever,TST

andSE

were

sign

ifican

tlyincrea

sedrelative

toplaceb

oforalldo

ses,

P,

0.00

01.

Wak

etimedu

ring

sleepwere

sign

ifican

tlyredu

cedat

alldo

ses,

P,

0.00

01.

Num

berof

AEswas

similar

betw

een

placeb

oan

dDXP

andweresimilar

betw

eenDXP

doses.

Low

-doseDXP

iseffective

atredu

cingsymptom

sof

insomnia.

Italso

increa

sesSE.D

XPseem

spa

rticularly

effectiveat

maintaining

sleep.

Yeu

nget

al.

(201

5).18

Varied

Systematic

review

andmeta-

analysis

ofnine

placeb

o-controlled

RCTs.

Pooledresu

ltswerelargelyno

trepo

rted

dueto

heteroge

neity;

howev

er,theau

thorswereab

leto

conc

lude

thesign

ifican

tefficacy

and

safety

ofDXP3–

6mgforon

eto

two

nigh

ts.

Inyo

ungan

dmiddle-ag

edad

ults,the

incide

nce

ofan

yAEswere27

%,

35%,a

nd32

%in

placeb

o,DXP3mg/

day(R

R=1,27

,95

%CI=0.8,

2.1,

P=0.29

),an

dDXP

6mg/da

y(R

R=1.30

,95

%CI0.8,

2.1,

P=0.29

).Com

mon

AEswere

head

ache

,somno

lenc

e,an

dna

usea

.Results

inolde

rad

ults

weresimilar.

Low

-doseDXP

iseffective

atredu

cingsymptom

sof

insomnia.


TABLE

12Sum

maryof

stud

iesas

sessingtheeffectsof

gaba

pentin

(GBP)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Brower

etal.(200

8)18

+Alcoh

olde

pende

nce

withcomorbid

insomnia

6-wkRCT

plus2-wkplaceb

olead

-inan

dfollow

upvisit

after6wk.

GBP

1500

mg/

dayvs.placeb

o.N

=21

.

60%

ofGBP

grou

prelaps

edto

hea

vydr

inkingby

12wkvs.

100%

oftheplaceb

ogrou

p,P=

0.04

.Treatmen

tgrou

pdidno

tpr

edictch

ange

sin

Sleep

Problem

sQue

stionn

aire

(SPQ)

score.

The

rewereno

sign

ifican

tpo

lysomno

grap

hicdifferen

ces

betw

eengrou

ps.

The

mostcommon

side

effects

attributed

toga

bape

ntin

vs.

placeb

o,resp

ective

ly,were

somno

lenc

e(thr

eesu

bjects

vs.

onesu

bject),he

adache

(thr

eesu

bjects

inea

chgrou

p),

dizziness(twosu

bjects

vs.on

esu

bject),indige

stion(twovs.

four

subjects),ne

rveor

mus

cle

pain

(twosu

bjects

vs.non

e).

GBP

isno

teffectiveat

redu

cing

symptom

sof

insomnia,

thou

ghit

delaye

dtheon

setto

hea

vydr

inking.

Foldv

ary-Sch

aefer

etal.(20

02)

20–46

Hea

lthypa

rticipan

tsRan

domized

stud

y.GBP

titrated

to18

00mg/da

yvs.

untrea

tedgrou

p.N

=19

.

GBP-treated

subjects

hadan

increa

sein

SWScompa

redwith

baseline

.Nodifferen

cein

othe

rpo

lygrap

hicva

riab

les.

GBP

subjects

hadminor

redu

ctions

inarou

sals,a

wak

enings,a

ndstag

esh

ifts

was

observed

intrea

ted

subjects.

One

patien

tex

perien

ced

dizzinessat

high

estdo

sean

dwas

trea

tedwith15

00mg/da

y.

GBP

may

beeffectiveat

increa

singSWSwithou

taffectingothe

ras

pectsof

sleep.

Karam

-Hag

ean

dBrower

(200

3)mea

n:44

S.D.:

14DSM-IV

alcoho

lde

pende

ncewith

persistent

insomnia

4–6-wkop

en-lab

elstudy

.GBP

300–

1800

mg/da

yvs.

traz

odon

e25

–30

0mg/da

y.N

=55

.

Bothgrou

pssh

owed

sign

ifican

tim

prov

emen

tin

sleepfrom

baseline

tofollow

up,P

,0.00

1forea

chgrou

pas

mea

suredby

theSPQ.Total

chan

gein

SPQ

scores

betw

eenthegrou

ps:G

BP

grou

pim

prov

edby

8.86

4.0

while

traz

adon

egrou

pim

prov

ed6.16

3.4,

P=0.02

3.

Bothmed

ications

werewell-

tolerated.

GBPis

effectiveat

redu

cing

symptom

sof

insomnia

inalcoho

lism

and

sign

ifican

tlymore

effectivethan

traz

odon

e.

Loet

al.(201

0)mea

n:43

.2S.D

.:15

.4Primaryinsomnia

4-wkop

en-lab

elstudy

.GBP

200–

900mg/da

y.N

=18

.Bypo

lysomnog

raph

y:GBPdidnot

sign

ifican

tlyim

prov

eSOL,

which

decrea

sedfrom

17.58to

14.58min.GBP

impr

oved

SE

from

80.00%

to87

.17%

,P

,0.05

.WASO

was

sign

ifican

tly

redu

cedfrom

16.45%

to7.84

%,

P,

0.05

.Sleep

stag

eN3

increa

sedfrom

10.47%

to17

.68%

,P

,0.00

5.

Prolactin

leve

lswere

sign

ifican

tlyredu

cedafter

GBP

trea

tmen

t;whether

the

effect

occu

rred

asaresu

ltof

GBP

was

uncertain.

GBPis

effectiveat

redu

cing

symptom

sof

insomnia

andincrea

sesslow

-wav

esleep.

Rob

insonan

dMalow

(201

3)Ped

iatric:

mea

n7.2

Refractoryinsomniain

childr

enwith

neu

rode

velopm

ental

orneu

rops

ychiatric

disord

ers

Ope

n-lab

elstudy

.GBP

6–15

mg/kg

perda

y.N

=23

.

Impr

oved

sleepwas

notedin

78%

ofch

ildr

en.

AEsno

tedin

sixch

ildr

en,m

ostly

agitationan

dworsene

dab

ility

tosleep.

GBPis

effectiveat

redu

cing

symptom

sof

insomnia

inch

ildr

enwith

neu

rode

velopm

entalan

dne

urop

sych

iatric

disord

ers.

Rosen

berg

etal.

(201

4)18

andolde

rOccas

ional

distur

bed

sleep

RCT

usinga5-hph

ase

adva

nceinsomniamod

el.

GBP

250mgvs.GBP

500mgvs.placeb

o.N

=37

7.

LPSwas

notsign

ifican

tlydifferen

tam

onggrou

ps.Mea

ntotalsleep

timewas

sign

ifican

tlygrea

ter

forthega

bape

ntin

grou

ps:3

11.4

68.4min

inplaceb

ogrou

p,35

6.56

7.5min

inGBP25

0mg,

and37

8.8min

inGBP

500mg

grou

p.Percent

slow

-wav

esleep

was

sign

ifican

tlygrea

terin

GBP

grou

ps,12

.6%,15

.4%,an

d17

.0%,resp

ective

ly.

4.2%

ofpa

rticipan

tsrepo

rted

atleas

ton

eAE,with1.6%

ofplaceb

opa

rticipan

ts,4.0%

ofGBP

250mg/da

ypa

rticipan

ts,

and7.2%

GBP

500mg/da

y.Themostcommon

AE

was

hea

dach

e.

GBPis

effectiveat

redu

cing

symptom

sof

insomnia

andincrea

sesslow

-wav

esleep.

230 Atkin et al.

12 weeks, 60% of the gabapentin group had relapsedcompared with 100% of the placebo group. Similarly, inthe single-dose study using a 5-hour phase advancemodel in patients with “occasional disturbed sleep,”gabapentin 250 mg/day and gabapentin 500 mg/daywere not significantly superior to placebo at reducinglatency to persistent sleep. However, the mean totalsleep time was significantly greater for the gabapentingroups: 311.4 [8.4] min in the placebo group versus356.5 [7.5]min in the gabapentin 250mg/day group (P#0.001 compared with placebo) and 378.7 [7.3] min in thegabapentin 500mg/day group (P# 0.001 comparedwithplacebo, P # 0.01 compared with gabapentin 250 mg/day). Wake after sleep onset was significantly improvedin the gabapentin groups, as was the proportion of timespent in SWS (stages 3 and 4) (Rosenberg et al., 2014).Finally, in the open-label comparison study of gabapen-tin and trazodone in alcoholism, gabapentin was signif-icantly more effective.6. Conclusion. A summary of the effects of gabapen-

tin on sleep architecture is presented in Table 2. Thereis some evidence that gabapentin is effective in thetreatment of insomnia disorder according to one open-label trial, although it did not significantly improvesleep onset latency (Lo et al., 2010).

B. Pregabalin

1. Mechanism of Action. Similar to gabapentin,pregabalin binds to a2d subunit-containing voltage-gated calcium channels (Taylor et al., 2007). Pregabalinalso modulates the influx of calcium at nerve terminals,which may accounts for its therapeutic benefit inneuropathic pain, seizures, and anxiety. The mecha-nism of action of pregabalin (Table 1) in improving sleephas not been completely elucidated, but it is known to bedifferent from benzodiazepines as pregabalin is notactive at GABA-A or benzodiazepine receptors (Tayloret al., 2007). Furthermore, although benzodiazepinestypically reduce SWS, pregabalin has been found toincrease it (Hindmarch et al., 2005). In rats, pregabalinhas been found to increase NREMS and REMS, whilemarkedly increasing the duration of NREMS episodesand reducing their number (Kubota et al., 2001). In onestudy, pregabalin increased NREMS in mice with aneuropathic pain-like condition, but not normal mice(Wang et al., 2015).2. Indications. Pregabalin is FDA approved for the

management of neuropathic pain associated with di-abetic peripheral neuropathy, the management of post-herpetic neuralgia, adjunctive therapy for adultpatients with partial onset seizures, the managementof fibromyalgia, and the management of neuropathicpain associated with spinal cord injury (US FDA, 2016).Clinical studies examining the hypnotic effects ofgabapentin are detailed in Table 13.3. Pharmacokinetics. Following oral administra-

tion, peak plasma concentrations of pregabalin occur

within 1.5 hours; its bioavailability is greater than orequal to 90% and is independent of dose (US FDA,2016). The half-life of pregabalin is about 6 hours.Taking pregabalin with food increases Tmax to approx-imately 3 hours and reduces Cmax by 25%–30%, al-though pregabalin can be taken with or without food. Itdoes not bind to plasma proteins and undergoes negli-gible metabolism in humans (US FDA, 2016). Oralclearance tends to decrease with increasing age.

4. Results in Insomnia Disorder. No studies ofpregabalin as a treatment of insomnia disorder wereidentified.

5. Other Results. Three reviews were found analyz-ing the use of pregabalin in patients with insomnia: intwo, patients were primarily diagnosed with general-ized anxiety disorder (Montgomery et al., 2009;Holsboer-Trachsler and Prieto, 2013), and in one,patients were primarily diagnosed with fibromyalgia(Russell et al., 2009). In the most recent review, pooleddata from four RCTs (N = 1354) established that amongpatients with severe difficulty in falling asleep, re-mission was observed in 54.0% of the pregabalin groupversus 29.8% of placebo group (Holsboer-Trachsler andPrieto, 2013). In those with severe difficulty in stayingasleep, remission was observed in 54.2% of pregabalingroup versus 26.7% of placebo group. Finally, in thosewith severe difficulty associated with waking up tooearly, remission was observed in 59.4% of pregabalingroup versus 34.6% of placebo group. The fibromyalgiastudy (N = 1493, two RCTs) likewise found thatpregabalin was significantly superior to placebo inreducing the burden of insomnia symptoms as mea-sured using the Sleep Quality Diary and MedicalOutcomes Study Subscales of Sleep Disturbance, Quan-tity of Sleep, and Sleep Problems Index (Russell et al.,2009). For more information about these psychometricscales, see Smith and Wegener (2003).

6. Conclusion. A summary of the effects of pregaba-lin on sleep architecture is presented in Table 2. Thereis good evidence based on two reviews (Montgomeryet al., 2009; Holsboer-Trachsler and Prieto, 2013) thatpregabalin is effective at reducing symptoms of in-somnia in generalized anxiety disorder. There is alsogood evidence based on one review (Russell et al., 2009)that pregabalin is effective at reducing symptoms ofinsomnia in fibromyalgia. Based on these same reviews,there is weak evidence that pregabalin is effective in thetreatment of insomnia disorder.

VIII. Atypical Antipsychotic Drugs

Sedating atypical antipsychotics, particularly quetia-pine, are often used in the clinic for the management ofinsomnia disorder and insomnia symptoms that occurcomorbid to psychiatric illness (Pringsheim and Gard-ner, 2014). Although they are effective in the manage-ment of bipolar and psychotic disorders, systematic


TABLE

13Sum

maryof

stud

iesas

sessingtheeffectsof

preg

abalin

(PGB)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

DeHaa

set

al.(20

07)

19–67

Epileps

yan

dsu

bjective

sleep

distur

banc

es

4-wkRCTpa

rallel-group

stud

y.PGB

300mg/da

ytw

iceada

yvs.placeb

otw

iceada

y.N

=17

.

PGB

hadpo

sitive

effect

ondistur

bedsleepba

sedon

subjective

assessmen

ts(que

stionn

aires)

butnot

onpo

lysomno

grap

hicmea

sures.

PSG

redu

cedon

lythenu

mbe

rof

awak

enings

(P=0.04

vs.

placeb

o).

Mildto

mod

erate.

Hea

dach

ewas

themostfreq

uen

tAE.Other

AEsweredizzinessan

dsomno

lenc

e.

PGB

impr

oves

sleepcontinuity

andsu

bjective

sleepqu

ality

inep

ilep

ticpa

tien

tswith

sleepcomplaints.

Hindm

arch

etal.

(200

5)18

–50

Hea

lthyad

ult

volunteers

Ran

domized

,do

uble-blind

,placeb

o-an

dactive

-controlled

,three-way

crossove

r.PGB

150mgthree

times

ada

yvs.alpr

azolam

1mgthreetimes

ada

yvs.

placeb

othreetimes

ada

yfor

3da

ys.N

=24

.

PGB

increa

sedTST,stag

eN3,

andsleepefficien

cy,an

dde

crea

sedSOL

andREM

sleep.

NS

PGB

hassign

ifican

teffectson

thesleepof

healthyhu

man

sthat

aredifferen

tfrom

those

ofBZD

;pa

rticularly,it

increa

sesSWSan

dsleep

continuity.

Holsb

oer-Trach

sler

etal.(20

13)

NS

Gen

eralized

anxiety

disord

erRev

iew

ofseve

nRCTs.

PGB

150–

600mg/da

yvs.placeb

o.Pooledremission

data

ininsomniasymptom

sfrom

four

4–6wkRCTs(N

=13

54):

“Sev

ere”

difficulty

offalling

asleep

,remission

observed

in54

.0%

ofPGB

grou

pvs.29

.8%

ofplaceb

ogrou

p;“sev

ere”

difficulty

instay

ingas

leep

,remission

observed

in54

.2%

ofPGB

grou

pvs.26

.7%

ofplaceb

ogrou

p;“sev

ere”

difficulty

withwak

inguptoo

early,

remission

observed

in59

.4%

ofPGB

grou

pvs.34

.6%

ofplaceb

ogrou

p.

Mostfreq

uent

adve

rseeffects,

like

somno

lenc

ean

ddizziness,

are

mostcommon

infirst2wkof

therap

y.The

incide

nceof

somno

lenc

eas

anAEin

patien

tswithmod

erateto

seve

reinsomniawas

lower

than

for

benz

odiazepine

s:PGB

150mg/

day:

24.4%,PGB

300-45

0mg/

day:

26.2%,PGB

600mg/da

y:31

.5%,alpr

azolam

/lorazepa

m:

54.2%,placeb

o:7.8%

.

PGB

iseffectiveat

redu

cing

symptom

sof

insomnia

inge

neralizedan

xietydisord

er.

Mon

tgom

eryet

al.

(200

9)Gen

eralized

anxiety

disord

erRev

iew

ofsixRCTs.

N=18

54.

Inpa

tien

tspr

esen

ting

withhigh

insomnia,

PGB

prod

uced

sign

ifican

tlygrea

ter

impr

ovem

enton

HAM-A

total

scores:PGB

300–

450mg/da

y(2

13.1

60.6);PGB

600mg/

day(2

11.2

60.5)

dose

grou

pscompa

redwithplaceb

o(2

8.36

0.5;

P,

0.00

01for

both

compa

risons

).PGB

150mg/da

ywas

not

sign

ifican

t(2

9.96

0.7;

P=0.05

1).

Total

discon

tinu

ations

werelower

than

placeb

o(25.9%

)for

preg

abalin

150mg/da

y(16.4%

)an

d30

0–45

0mg/da

y(16.4%

),no

nsignificantly

high

erfor

preg

abalin

600mg(27.6%

),an

dsign

ifican

tlyhigh

erfor

alpr

azolam

/lorazepa

m(38.0%

,resp

ective

ly;P

,0.05

.

PGB

300–

600mg/da

yis

effectiveat

redu

cing

symptom

sof

anxietyin

patien

tspr

esen

ting

with

gene

ralizedan

xietydisord

erwithhigh

leve

lsof

insomnia.

Russellet

al.(200

9)18

+Fibromya

lgia

Rev

iew

oftw

oRCTs.

PGB

300,

450,

or60

0mg/da

yvs.

placeb

o.N

=14

93.

Bothstud

iesfoun

dsign

ifican

tim

prov

emen

tin

PGB

grou

prelative

toplaceb

ogrou

pon

:Sleep

Qua

lity

Diary

andMOS

Sub

scales

ofSleep

Disturban

ce,Qua

ntityof

Sleep

,an

dSleep

Problem

sIn

dex.

Pooledresu

ltsno

tlisted

.

Not

analyz

ed.

PGB

iseffectiveat

redu

cing

symptom

sof

insomnia

infibrom

yalgia.

232 Atkin et al.

reviews have found a lack of evidence for the use ofsedating atypical antipsychotics and explicitly recom-mend against prescribing them for insomnia disorder(Thompson et al., 2016). The 2016meta-analysis acknowl-edges that the use of atypical antipsychotics may beappropriate in patients who have failed other treatmentmodalities and who have a comorbid condition that couldbenefit from the primary action of the drug (based onconsensus of experts in sleep medicine). Similarly, guide-lines for the treatment of chronic insomnia report in-sufficient evidence for atypical antipsychotics as first-linetherapy (Schutte-Rodin et al., 2008), but state that themedications may be suitable for patients with comorbidinsomnia who may benefit from the primary action ofthese drugs as well as from the sedating effect.

A. Olanzapine

1. Mechanism of Action. Olanzapine is an atypicalantipsychotic with affinity for the dopamine D1, D2, andD4 receptors; the serotonin 5-HT2A, 5-HT2C, and 5-HT3

receptors; the a1-adrenergic receptor; the histamine H1

receptor; and five muscarinic receptor subtypes(Bymaster et al., 1996). Its hypnotic effects are probablyattributable to its strong antagonism of the H1 antag-onism as well as its antagonism of serotonin receptors.In an assay of compounds tested at the histamine H1

receptor, olanzapine was the most potent compoundRichelsen and Souder (2000) had tested of any class ofcompounds. Olanzapine seems to specifically increaseSWS (Salin-Pascual et al., 1999; Giménez et al., 2007;Kluge et al., 2014). Main molecular targets of olanza-pine are summarized in Table 1.2. Indications. Olanzapine is FDA approved for the

treatment of schizophrenia in adults and adolescents;for the acute treatment of manic or mixed episodesassociated with bipolar I disorder and the maintenancetreatment of bipolar I disorder in adults and adoles-cents; and, as an intramuscular injection, for thetreatment of acute agitation associated with schizo-phrenia and bipolar I mania (US FDA, 2009). Clinicalstudies examining the hypnotic effects of olanzapine aredetailed in Table 14.3. Pharmacokinetics. Olanzapine reaches peak con-

centrations about 6 hours following oral administration,and its elimination half-life ranges from 21 to 54 hours,with a mean of 30 hours (US FDA, 2009). It is eliminatedextensively by first-passmetabolism: about 40% of an oraldose is metabolized before it reaches the systemic circu-lation. Olanzapine is extensivelymetabolized byCYP1A2,CYP2D6, and the flavinmonooxygenase system, althoughits metabolites do not display pharmacological activity atnormal concentrations (US FDA, 2009). Its pharmacoki-netics are not affected by food. The drug is 93% bound toplasma protein. Clearance of olanzapine is approximately30% lower in women than in men, and the eliminationhalf-life of olanzapine is about 1.5 times higher in subjectsgreater than 65 years old.

4. Results in Insomnia Disorder. No studies ofolanzapine as a treatment of insomnia disorder wereidentified.

5. Other Results. Two studies that examined olan-zapine’s effect on sleep (Salin-Pascual et al., 1999;Sharpley et al., 2000) and three studies on olanzapineas a treatment of secondary insomnia were identified(Jakovljevi�c et al., 2003; Khazaie et al., 2010, 2013). Ofthe studies analyzing olanzapine’s effect on sleep, bothwere small: one was an open-label study conducted in20 patients with schizophrenia, during which polysom-nographic recordings were taken for 5 days, withpatients only receiving olanzapine on two nights(Salin-Pascual et al., 1999) and one was a one-dosecrossover RCT conducted in nine healthy male partic-ipants, with 7–14 days washout between doses(Sharpley et al., 2000). The crossover RCT examinedolanzapine 5, 10 mg/day or placebo, whereas the studyin patients with schizophrenia examined olanzapine10 mg/day. Both studies found that olanzapine pro-foundly increased slow-wave sleep and increased totalsleep time as acute treatment.

Of the studies in secondary insomnia, one was con-ducted in patients suffering from treatment-resistantposttraumatic stress disorder (PTSD) (Jakovljevi�c et al.,2003), whereas the other two were in patients withparadoxical insomnia, also known as sleep state mis-perception (Khazaie et al., 2010, 2013). The first studywas in patients suffering from intractable PTSD inwhich open-label olanzapine was added to their currentmedications (Jakovljevi�c et al., 2003). The patients hadrecurrent nightmares and insomnia resistant to numer-ousmedications. In all five cases, olanzapine resulted ina significant improvement in their symptoms. Onerandomized, open-label studywas conducted in patientsdiagnosed with paradoxical insomnia, or sleep-statemisperception (Khazaie et al., 2013). Patients sufferingfrom this disorder complain of difficulties with initiat-ing and maintaining sleep; however, the hallmark ofparadoxical insomnia is that objective polysomno-graphic measures find that the patients are gettingsufficient sleep. In this study, the investigators followedup on a case report study they had published in 2010 -(Khazaie et al., 2010), in which they reported successfultreatment of recalcitrant, paradoxical insomnia witholanzapine in a single patient. The group’s larger studycompared treatment with two different atypical anti-psychotics: olanzapine and risperidone. They foundthat, although both treatments were associated withsignificant improvements in subjective sleep quality,olanzapine was significantly superior to risperidone, asmeasured using the Pittsburgh Sleep Quality Index(PSQI) (Buysse et al., 1989).

6. Conclusion. A summary of the effects of olanza-pine on sleep architecture is presented in Table 2. Thereis weak evidence that olanzapine acutely increasesslow-wave sleep and total sleep time (Salin-Pascual


TABLE

14Sum

maryof

stud

iesas

sessingtheeffectsof

olan

zapine

(OLA)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Jako

vljevi� cet

al.

(200

3)28

–50

Treatmen

t-resistan

tPTSD

withnigh

tmares

andinsomnia

Cas

eseries.OLA

adde

dto

curren

ttrea

tmen

tregimen

.N

=5.

Allfive

patien

tsim

prov

edrapidly

aftertrea

tmen

tinitiation

with

olan

zapine.

NoAEswererepo

rted

.OLA

may

beeffectiveat

redu

cing

sleep

distur

banc

esin

PTSD.

Kha

zaie

etal.(20

13)

60Parad

oxical

insomnia

Cas

erepo

rt.OLA

5mg/da

yad

dedto

trea

tmen

tregimen

.N

=1.

After

6wk,

OLA

trea

tmen

tresu

lted

incompleteremission

ofsymptom

s.

Non

elisted

.OLA

may

beeffectiveat

redu

cingsymptom

sof

parado

xicalinsomnia.

Kha

zaie

etal.(20

13)

Mea

n:53

.4;

S.D

.:14

.4Parad

oxical

insomnia

8-wkrand

omized

,op

en-lab

eltrial.OLA

10mg/da

yvs.

risp

eridon

e4mg/da

y.N

=29

.

Sleep

qualitymea

suredwiththe

Pittsbu

rghSleep

Qua

lity

Inve

ntorysh

owed

sign

ifican

tim

prov

emen

tin

both

trea

tmen

tgrou

ps,thou

ghim

prov

emen

tin

OLA

grou

pwas

supe

rior

torisp

eridon

egrou

p.In

OLA

grou

p,ba

selinemea

nwas

11.8

62.3an

dtrea

tmen

tmea

nwas

2.66

1.6,

P,

0.00

1.In

risp

eridon

egrou

p,ba

seline

mea

nwas

11.1

62.4an

dtrea

tmen

tmea

nwas

56

3.8,

P,

0.00

1.Betweengrou

pscompa

risonyielde

dP

,0.04

.

NoAEswererepo

rted

.OLA

iseffectiveat

redu

cingsymptom

sof

parado

xicalinsomnia.

Kluge

etal.(20

14)

18–65

Sch

izop

hrenia

andreview

oftheliterature

6-wkRCTsing

lecenter.O

LA

5-25

mg/da

yvs.clozap

ine

100–

400mg/da

y.During

thefirst2wk,

thedo

serang

ewas

restricted

(OLA

10–15

mg/da

y,clozap

ine

25–20

0mg/da

y).N

=30

.

OLA

andclozap

ineincrea

sedTST

andsleepefficien

cy,an

dde

crea

sedSOL.Con

cern

ing

sleepstag

es,OLA

increa

sed

SWSan

dde

crea

sedREM

slee

p.

Noclinically

releva

ntsymptom

sof

restless

legs

synd

romewere

observed

.Noothe

rAEswerean

alyz

ed.

OLA

iseffectivein

impr

ovingsleepin

patien

tswith

schizop

hrenia.

Salin-Pas

qual

etal.

(199

9)Mea

n:33

.6;

S.D

.:10

.7Sch

izop

hren

iaFive-nigh

top

en-lab

elpo

lysomno

grap

hicstud

ywithOLA

10mg/da

yad

ministeredfortw

onigh

ts.N

=20

.

OLA

enha

nced

slow

wav

esleep

andincrea

sedtotalsleeptime.

REM

dens

ityincrea

sedan

dstag

e1de

crea

sedwithOLA.

Non

elisted

.OLA

may

increa

seslow

wav

eslee

pan

dtotal

sleeptimein

schizop

hrenia.

Sharpley

etal.

(200

0)33

–60

Hea

lthysu

bjects

One

-dosecrossove

rRCT.

OLA

5mg/da

yvs.OLA

10mg/da

yvs.placeb

o.N

=9.

OLA

subs

tantiallyincrea

sedslow

wav

esleep,

by59

.1%

and83

.3%

forthe5an

d10

mg/da

ydo

ses,

resp

ective

ly.OLA

increa

sed

totalsleeptime.

Non

elisted

.OLA

increa

sesslow

wav

eslee

pan

dtotal

sleeptimein

healthy

subjects.

234 Atkin et al.

et al., 1999; Sharpley et al., 2000), although this effecthas not been confirmed in patients with insomnia.There is also evidence that olanzapine may be usefulin 1) the treatment of insomnia associated with PTSD(Jakovljevi�c et al., 2003) based on a case series and 2)paradoxical insomnia, based on a case report (Khazaieet al., 2010) and a randomized, open-label trial (Khazaieet al., 2013).

B. Quetiapine

1. Mechanism of Action. Quetiapine, a dibenzothia-zepine derivative, is the atypical antipsychotic thatdisplays the lowest D2 affinities (Richelson and Souder,2000; Comai et al., 2012b). It shows antagonism atmultiple neurotransmitter receptors, mainly 5-HT2A,5-HT2c, H1, and D2 (Table 1). Its sedative and hypnoticproperties are attributable to its antagonism of thehistamine H1 receptor and various serotonin receptors.Inmonkeys, neither acute nor chronic administration ofquetiapine improved sleep efficiency, whereas the firstnight after discontinuation, subjects had significantlydecreased sleep efficiency and increases in nighttimeactivity (Brutcher and Nader, 2015).2. Indications. Quetiapine is FDA approved for the

treatment of schizophrenia in adults and adolescents,the treatment of bipolar mania in children and adoles-cents, and the treatment of bipolar depression in adults.Clinical studies examining the hypnotic effects ofquetiapine are detailed in Table 15.3. Pharmacokinetics. Quetiapine fumarate is rap-

idly absorbed after oral administration, reaching peakplasma concentrations within 1.5 hours (US FDA,2017). The drug is 83% bound to serum proteins(DeVane and Nemeroff, 2001). Administration withfood increases Cmax and AUC by 25% and 15%, re-spectively. The drug is mainly eliminated throughhepatic metabolism, specifically CYP3A4, and itsmean terminal elimination half-life is 6 hours. Oralclearance is reduced by 40% in subjects greater than65 years of age, although sex does not affect itspharmacokinetics.4. Results in Insomnia Disorder. One RCT was

identified in patients diagnosed with primary insomnia(Tassniyom et al., 2010). Surprisingly, although obser-vational evidence suggests that atypical antipsychoticslike quetiapine are increasingly prescribed for insom-nia, the 2010 study was the only RCT that was found inthe literature of an atypical antipsychotic in primaryinsomnia, and it had a small sample size of only13 patients who completed the study (Tassniyomet al., 2010). In the RCT, quetiapine 25 mg/day treat-ment was not significantly superior to placebo at in-creasing sleep time and reducing latency to sleep,although there was a trend toward the superiority ofquetiapine (Tassniyom et al., 2010).In contrast, an open-label trial of quetiapine 25–

75 mg/day found that the drug was effective at reducing

symptoms of insomnia, increasing total sleep time andreducing PSQI (Wiegand et al., 2008).

5. Other Results. Eleven other studies of quetiapinethat included sleep parameters were identified: fivewere open label (Juri et al., 2005; Todder et al., 2006;Baune et al., 2007; Pasquini et al., 2009), three wererandomized, placebo-controlled trials (Cohrs et al.,2004; Garakani et al., 2008; McElroy et al., 2010), onewas a review (Anderson and Vande Griend, 2014)pooling many of the studies cited here, one was anaturalistic study (�Sagud et al., 2006), one was a posthoc analysis of two RCTs (Endicott et al., 2008), and onewas a retrospective study (Terán et al., 2008).

One RCT in 14 healthy male subjects found thatquetiapine 25 and 100 mg/day significantly improvedsleep induction and sleep continuity under standardand acoustic stress conditions (Cohrs et al., 2004).Active treatment with quetiapine also increased totalsleep time, sleep efficiency, and subjective sleepquality.

In contrast to the results of the RCT in primaryinsomnia, the open-label studies in other conditionswere generally positive, although they were conductedin a wide range of patient populations. The includedstudies analyzed patients diagnosed with Parkinson’sdisease, treatment-resistant depression, bipolar disor-der, breast cancer with tamoxifen-induced insomnia,and insomnia induced by detoxification from substanceabuse. Unfortunately, a retrospective chart review (N =43) found that quetiapine prescribed for insomnia at amean dose of 120.3 6 58.6 mg/day had adverse meta-bolic side effects (Cates et al., 2009). However, neitherthe RCT of quetiapine 25 mg/day study (Tassniyomet al., 2010) nor the open-label trial of quetiapine 25–75 mg/day (Wiegand et al., 2008) reported the rate ofmetabolic side effects, and the retrospective review didnot perform subgroup analysis of the patients taking25 mg/day (N = 4 at baseline).

6. Conclusion. A summary of the effects of quetia-pine on sleep architecture is presented in Table 2.There is moderate evidence that quetiapine is notsignificantly effective for the treatment of primaryinsomnia, based on one small RCT (Tassniyom et al.,2010). Randomized studies support the usefulness ofquetiapine in insomnia that is secondary to conditionsfor which quetiapine has an FDA-approved indication,like bipolar depression or unipolar depression (asaugmentation). There is Level 1b evidence based ontwo RCTs (Calabrese et al., 2005; McElroy et al., 2010)that quetiapine is effective in the treatment of in-somnia secondary to bipolar depression. There is Level1b evidence based on one RCT (Garakani et al., 2008)and three open-label trials (�Sagud et al., 2006; Todderet al., 2006; Baune et al., 2007) that quetiapine asaugmentation of antidepressants is effective in re-ducing symptoms of insomnia in treatment-resistantdepression.


TABLE

15Sum

maryof

stud

iesas

sessingtheeffectsof

quetiapine

(QTP)on

sleep

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Ande

rson

and

Van

deGrien

d(201

4)

Varied

Varied

Rev

iew

oftheliterature

ofqu

etiapine

inthetrea

tmen

tof

insomnia.

Varied

Given

QTP’sad

verseeffects

profile(see

RCTsab

ove),

QTP’sbe

nefits

have

not

been

prov

ento

outw

eigh

therisk

.

Rob

uststud

iesev

alua

ting

quetiapineforinsomnia

arelack

ing.

Bau

neet

al.(20

07)

Males:mea

n48

.6,S

.D.1

2.9;

Fem

ales:m

ean

50.5,S.D

.13.2

Treatmen

t-resistan

tun

ipolar

orbipo

lar

IIde

pression

4-wkop

en-lab

elin-patient

trial

ofQTP

augm

entation

ofve

nlafax

ineor

escitalopr

am.

Mea

nQTPdo

se34

0mg/da

y,max

800mg/da

y.N

=27

.

PSQItotalscorewas

8.86

2.8at

baseline

and5.26

1.8at

week4,

P=0.00

.PSQIda

ytim

esleepine

sswas

1.96

0.8at

baseline

and0.8

60.7at

week4,

P=0.00

.

Duringthe4-wkstudy

,ne

ithe

rad

verse

metab

olic

orclinical

even

tsno

rsign

ifican

tweigh

tga

inwere

record

ed.

QTPis

effectiveat

redu

cing

symptom

sof

insomniain

patien

tswithde

pression

.

Calab

rese

etal.

(200

5)18

–65

Typ

eIor

Typ

eII

bipo

larde

pression

8-wkRCT.QTP

300vs.

600mg/da

yvs.placeb

o.N

=54

2.

Sleep

difficulties

weremod

erateto

seve

reat

baseline

.PSQItotal

scoreat

last

assessmen

tim

prov

edby

5.16

points

withQTP30

0mg/

dayan

d5.46

points

withQTP

600mg/da

y,compa

redwith2.94

points

forplaceb

o,P

,0.00

1for

both

dosa

gesrelative

toplaceb

o.

QTP60

0mg/da

yex

perien

ced1.6kg

ofweigh

tga

invs.1.0kg

inthe30

0mg/da

ygrou

pan

d0.2kg

intheplaceb

ogrou

p.Mea

nch

ange

infastinggluc

osewas

66

17mg/dl

inQTP

600mg/

day,

36

13mg/dl

inQTP

300mg/da

y,an

d46

26mg/dl

intheplaceb

ogrou

p.

QTPis

effectiveat

redu

cing

symptom

sof

insomniain

bipo

larde

pression

.

Coh

rset

al.(20

04)

19–33

Hea

lthysu

bjects

Nine-nightRCT.Threestudy

period

slasting3da

ys,w

itha

4da

ywas

hout.QTP25

mg/

dayvs.QTP

100mg/da

yvs.

placeb

o.N

=14

.

Bothdo

sesQTPsign

ifican

tly

impr

oved

LOSan

dsleep

continuityunde

rstan

dard

and

acou

stic

stress

cond

itions

.Total

sleeptimean

dSE

increa

sed.

Significant

increa

sein

period

iclegmov

emen

tswas

observed

withQTP

100mg/da

y.

QTPincrea

sessleepin

healthyvo

lunteers.

Garak

aniet

al.

(200

8)18

–65

Major

depr

essive

disord

er8-wkRCT.Q

TP25

–10

0mg/da

y+fluo

xetine

20–40

mg/da

yvs.placeb

o+fluo

xetine

.N

=11

4.

Mixed

-effectregression

mod

elssh

owthat

QTP+fluox

etinegrou

pim

prov

edsign

ifican

tlymore

rapidlyon

insomniascores.From

baseline

tofirstfollow

upvisit,P=

0.00

055;

tosecond

follow

upvisit,

P=0.00

04;tothirdfollow

upvisit,

P=0.01

.

Sed

ationwas

more

prev

alen

tin

theQTP

+fluox

etinegrou

p,P

=0.00

6.

QTPis

effectivein

redu

cing

symptom

sof

insomniain

patien

tswithde

pression

.

Keshav

anet

al.

(200

7)QTP

grou

p:mea

n36

.1,

S.D

.9.8

Sch

izop

hren

iaCross-section

al,QTP31

3.33

622

8.71

mg,

vs.risp

eridon

e3.25

62.12

vs.ne

urolep

tic-

naïvepa

tien

ts.N

=39

(patientsalread

ystab

ilized

onQTPor

risp

eridon

e),N

=31

(neu

roleptic-naïve

patien

ts)

REM

coun

tswereelev

ated

inthe

QTPthan

inne

urolep

tic-na

ïve

patien

ts.QTPan

drisp

eridon

etrea

tedpa

tien

tsha

dmore

prom

inen

tSWSan

d%

ofstag

eN2,

andredu

cedREM

slee

pthan

neve

r-trea

tedschizoph

renia

subjects.

Not

analyz

ed.

QTPsu

ppresses

REM

slee

pin

patien

tswith

schizoph

renia.

Its

therap

euticsign

ifican

cerequ

ires

furthe

rinve

stigation.

Juri

etal.(20

05)

Mea

n:67

.6,

S.D

.:8.4

Parkins

on’sdiseas

ewitho

utps

ycho

sis

withinsomnia

12-w

kop

en-lab

eltrial.Mea

nQTPdo

se31

.9mg/da

y,range

12.5–50

mg/da

y.N

=14

.

PSQIredu

cedby

mea

n6

S.D

.3.8

63.9,

P,

0.01

.SOL

redu

cedfrom

826

65.4

minutes

to28

.66

22.7

onlast

visit,P

,0.05

.

Twodiscon

tinuationsdu

eto

restless

legs

synd

rome

that

worsened

since

the

beginn

ingof

trea

tmen

t.Twosu

bjects

also

repo

rted

worsene

dsleepine

ssdu

ring

the

day.

Noworseningof

motor

symptom

sor

orthostaticsymptom

s.

QTPis

effectiveat

redu

cing

symptom

sof

insomniain

Parkinson’sdiseas

epa

tien

tswithinsomnia.

(con

tinued

)

236 Atkin et al.

TABLE

15—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

McE

lroy

etal.

(201

0)18

+Typ

eIor

Typ

eII

bipo

larde

pression

8-wkRCT.Q

TP30

0mg/da

yvs.

QTP60

0mg/da

yvs.

paroxe

tine20

mg/da

y.N

=74

0.

MADRSitem

4(red

uced

sleep)

impr

oved

sign

ifican

tlymorein

both

QTParmsthan

inplaceb

o.In

contrast,thepa

roxe

tine

arm

was

notsign

ifican

tlysu

perior

toplaceb

oin

redu

cing

item

four

scores.

AEslead

ingto

trea

tmen

tdiscon

tinu

ationwere

repo

rted

in9.1%

ofQTP

300mg/da

y,12

.3%

ofQTP

600mg/da

y,13

.2%

ofpa

roxe

tine

,and

8.1%

ofplaceb

o.In

cide

nceof

seriou

sAEslowestin

QTP

300mg/da

y,while

thosetrea

tedwith

paroxe

tine

disp

laye

dthe

high

est.

QTPis

moreeffectivethan

paroxe

tine

atredu

cing

symptom

sof

insomniain

bipo

larde

pression

.

Pas

quiniet

al.

(200

9)19

–65

Breas

tcanc

erwith

insomnia

indu

ced

bytamox

ifen

Retrosp

ective

open

-lab

eltrial.

QTPdo

se,20

0mg/da

y.N

=6.

Weigh

tincrea

sedby

4.9po

unds

(P=

0.03

7).BMIincrea

sedby

.Eight

points

(P=0.04

8).The

rewereno

sign

ifican

tdifferen

cesbe

tween

baseline

anden

dpoint

metab

olic

parameterswhen

exam

ined

byba

seline

BMI,

agecatego

ry,

psychiatricdiag

nosis,

orconc

omitan

tps

ycho

trop

icmed

ication.

Rep

ortedside

effects

includ

edweigh

tga

in(N

=2)

anddizziness

(N=1).

QTPincrea

sesweigh

tga

inin

patien

tstrea

tedfor

insomnia.

Rob

ertet

al.(20

05)

49–68

Sleep

disturban

cesin

comba

tve

terans

withDSM-IV

PTSD

6-wkop

en-lab

eltrial.QTP

mea

n10

06

70mg/da

y,rang

e25

–30

0mg/da

y.N

=19

.

Globa

lPSQIscores

decrea

sed

sign

ifican

tly,

15.826

2.72

atba

seline

to7.89

65.15

atweek6,

P,

0.00

1.Sleep

quality

impr

oved

,P=0.00

6.Sleep

latenc

yim

prov

ed,P

=0.00

2.Total

sleep

timeincrea

sedfrom

4.06

1.0to

6.06

1.8hpe

rnigh

t,P

,0.00

1.

Sed

ationwas

repo

rted

by36

.8%

ofpa

tien

ts,lea

ding

todiscon

tinu

ationin

one

patien

t.

QTPmay

redu

cesymptom

sof

insomniain

patien

tswithPTSD.

� Sag

udet

al.(20

06)

18+

Treatmen

t-resistan

tDSM-IV

depr

ession

20-w

kop

en-lab

eltrialof

QTP

asau

gmen

tation

ofan

tide

pressa

nts.

Mea

nQTP

dose

315mg/da

y.N

=14

.

QTP

sign

ifican

tlyim

prov

edthe

anxietyan

dinsomniasu

bscalesof

theHAM-D

.In

somniascores

ofHAM-D

was

sign

ifican

tlyredu

ced

from

baseline

after20

wkof

trea

tmen

t,P

,0.05

.

Thr

eepa

tien

tsha

dhyp

oten

sion

andtw

ohad

daytim

eseda

tion

,tran

sien

tan

dmild.

QTPis

effectivein

redu

cing

symptom

sof

insomniain

patien

tswithde

pression

.

Tas

sniyom

etal.

(201

0)25

–62

Primaryinsomniaby

DSM-IV

2-wkRCT.QTP

25mg/da

yvs.

placeb

o.N

=16

.In

crea

sesin

sleeptime:

placeb

o=

72.24minutes

vs.QTP=

124.92

minutes

(P=0.19

3).

Red

uctionsin

SOL:p

lacebo

=23

.72minutes

vs.QTP=

96.16minutes

(P=0.07

0).Trend

forim

prov

emen

twas

show

nthou

ghdidnot

reactsign

ifican

tdifferen

ce.

Twopa

tien

tsin

QTP

grou

prepo

rted

drylips

,dr

ytongu

e,an

dmorning

drow

sine

ss.

QTPmay

beeffectiveat

redu

cing

symptom

sof

insomnia.

Terán

etal.(200

8)NS

Insomnia

during

detoxification

insu

bstanc

eab

users

Retrosp

ective

chartreview

.QTP25

–22

5mg/da

y.N

=52

med

ical

record

s.

Globa

lSpieg

elSleep

Que

stionn

aire

(SSQ)scores

sign

ifican

tly

impr

oved

throug

hout

the60

-day

follow

uppe

riod

,P

,0.00

1.Greatestim

prov

emen

toccu

rred

infirstweekof

trea

tmen

tan

dremaine

dcons

tant

therea

fter.

Nopa

tien

tsdr

oppe

dou

tdu

eto

AEs.

Most

common

AE

was

dry

mou

th(34.6%

).

QTPis

effectiveat

redu

cing

symptom

sof

insomnia

during

detoxification

from

subs

tanc

eab

use.

(con

tinued

)


IX. Discoveries, Novel Pathways, and Pipelines

The discoveries and pipelines in this section, con-structed using data from a custom search of theCortellis database, are an up-to-date (as of February2017) snapshot of the current state of the research anddevelopment of insomnia medications.

A. Discoveries

1. Adenosine Receptor Agonist. YZG-331 is a prom-ising sedative hypnotic and adenosine analog thatexerts its effects by binding to the adenosine receptor.(See the Other Receptors section for a review of thepharmacology of A1A and A2A.)

2. Casein Kinase-1d/«. The casein kinase-1d andcasein kinase-1« proteins are essential elements of themolecular oscillators known as circadian clocks (Leeet al., 2009). Their importance to the functioning of themammalian circadian rhythm has spurred interest incasein kinase-1d/« inhibitors as potential clinical treat-ments of sleep disorders and other central nervoussystem disorders including neurodegenerative condi-tions (Perez et al., 2011).

3. Selective Melatonin MT2 Receptors. Studies onmelatonin MT1 knockout, MT2 knockout, and doubleMT1-MT2 knockout mice have demonstrated that thesetwo receptors have opposing or complementary func-tions. Whereas MT2 receptor activation promotes SWS,MT1 decreases SWS and increases REMS (Ochoa-Sanchez et al., 2011; Ochoa-Sanchez et al., 2014). Thisevidence prompted the development of novel selectiveMT2 agonists as hypnotics. The compound UCM765 hasgreater MT2 receptor affinity (pKi = 10.18) than mela-tonin (pKi = 9.59) and has about 100-fold higher affinityfor the MT2 receptor than for the MT1 receptor (pKi =8.28). UCM924 also displays MT2 affinity (pKi = 10.2)that is 300-fold higher than forMT1 (pKi = 6.75), with anintrinsic activity for MT1: IAr-hMT1 = 0.1; and for MT2:IAr-hMT2 = 0.4 (Rivara et al., 2009).

Both UCM765 (Ochoa-Sanchez et al., 2011) andUCM924 (Ochoa-Sanchez et al., 2014) increase SWSduring the inactive phase of the day, without significantchange in REMS or sleep architecture. The congenernonselective MT1-MT2 receptor UCM971 did not alterthe 24-hour duration of wakefulness, NREMS, orREMS, but modified the number of episodes. MLTdecreased (237%) the latency to the first episode ofNREMS and enhanced the power of NREMS delta band(+33%), but did not alter the duration of any of the threevigilance states or modify the duration of SWS (Ochoa-Sanchez et al., 2014). These data confirm the impor-tance of targeting the MT2 receptor for hypnotic effects.UCM765 and UCM924 show a good safety profile andare currently under development for clinical studies.

4. Selective Orexin-2 Antagonist. Although dualorexin receptor antagonists like suvorexant are effec-tive at promoting sleep, selective orexin-2 receptor

TABLE

15—

Con

tinued

Study

Age

Diagn

osis

Design+Numbe

rof

Participa

nts

Results

Adv

erse

Eve

nts

Con

clusion

Tod

deret

al.

(200

6)21

–76

Treatmen

t-resistan

tunipo

laror

bipo

lar

depr

ession

compa

redwith

hea

lthy

controls

4-wkop

en-lab

elfollow

upstud

yof

QTP

augm

entation

ofan

tide

pressa

nts.

QTP

50–

800mg/da

y.N

=54

.

Objective

actigrap

hicsleepan

alysis:

nosign

ifican

tdifferen

cewas

foundbe

twee

nWee

ks1an

d4.

SE

didnot

chan

ge.Actua

lsleeptime

was

high

erat

alltimepo

ints

inpa

tien

tscompa

redwithcontrols,

howev

er,S

OL

was

sign

ifican

tly

high

erin

controls

compa

redto

patien

ts.S

ubjectivesleepan

alysis

withPSQI:

statistically

sign

ifican

tim

prov

emen

tsof

total

sleepscore,

qualityof

sleep,

daytim

esleepine

ss,be

tweenthe

weekbe

fore

admission

,Week1,

andWee

k2.

SOL

impr

oved

betw

eenWee

ks1an

d4.

Not

analyz

ed.

QTPmay

beeffectiveat

redu

cing

symptom

sof

insomniain

patien

tswith

depr

ession

.

Wiega

ndet

al.

(200

8)NS

Primaryinsomnia

6-wkop

en-lab

elstudy

.QTP

25–75

mg/da

y.N

=18

.Total

sleeptime(m

inute)

increa

sed

from

358.06

61.4

atba

seline

to39

5.66

62.3

at6w,P

=0.03

.SOL

(minute)

was

22.1

617

.0at

baseline

and24

.26

19.0

at6wk

(P=0.83

).PSQItotalscorewas

redu

cedfrom

13.1

62.3at

baseline

to6.86

3.3at

6wk,

P=

0.00

.

Dry

mou

than

dtran

sien

tha

ngov

ersymptom

swere

record

edmostfreq

uen

tly.

QTPis

effectiveat

redu

cing

symptom

sof

insomnia.

238 Atkin et al.

blockers may preserve sleep architecture to a greaterextent than dual antagonists (Bonaventure et al., 2015).Indeed, only orexin-2 but not orexin-1 is involved in theregulation of sleep (Dugovic et al., 2009). JNJ-42847922is a novel orexin-2 antagonist shown to reduce thelatency to NREM sleep and increase NREM sleep in thefirst 2 hours after administration, without affectingREM sleep in rats (Bonaventure et al., 2015). Impor-tantly, the compound has been shown to reduce time tosleep onset and increase total sleep time after 7 days ofchronic dosing (30 mg/kg). The compound did not pro-duce conditioned-place preference or increase dopaminerelease in the nucleus accumbens, indicating that itlacks intrinsic motivational properties, in contrast tozolpidem. In a Phase I study in healthy human subjects,JNJ-42847922 (10–80 mg/day) significantly increasedsomnolence: 22 of 26 subjects (85%) receiving JNJ-42847922 reported somnolence as an adverse event,whereas only 3 of 13 subjects (23%) receiving placebodid (Bonaventure et al., 2015). The compound’s phar-macokinetic profile in humans was favorable, with ahalf-life of 2 hours. One subject reported experiencingsleep paralysis after receiving the 80 mg/day dose.

B. Pipelines

1. Lumateperone. Lumateperone is a mechanisti-cally novel investigational antipsychotic drug with aunique pharmacological profile, showing very high5-HT2A blocking activity (Ki = 0.54 nM) relative to itsD2 modulating activity. The drug has a 60-fold differ-ence between its affinity for 5HT2A and D2 receptorscompared with a 12-fold difference for risperidone, a12.4-fold difference for olanzapine, and a 0.18-folddifference for aripiprazole (Davis et al., 2015; Snyderet al., 2015). Lumateroperone functions as a modulatorof the D2 receptor by partially agonizing presynaptic D2

receptors and antagonizing postsynaptic D2 receptors(Ki = 32 nM) (Snyder et al., 2015). Furthermore, thedrug blocks the serotonin transporter with strongaffinity (Ki = 62 nM) while having no affinity for theH1 histaminergic or muscarinic receptors (Snyder et al.,2015). Importantly, the drug’s D2 and SERT occupancyincrease with dose (Davis et al., 2015); at low doses, thedrug theoretically functions as a selective 5-HT2A

blocker.The company, Intra-Cellular Therapies (New York,

NY), suggests on their website that lower doses oflumateperone could be useful in the treatment of sleepdisorders, whereas higher doses are targeted to neuro-psychiatric disease. A Phase 2 study (N = 18) oflumateperone as a treatment of insomnia characterizedby sleep maintenance difficulties was discontinuedearly when the investigators found robust evidence ofefficacy, with increased SWS and decreased wake aftersleep time by polysomnography (Intra-Cellular Thera-pies, 2009). Furthermore, lumateperone did not impairnext-day cognition as measured by Leeds Psychomotor

Battery, Digit Symbol Substitution Test, or Word PairAssociates Test.

2. Piromelatine. Piromelatine is a unique drug thatcombines agonist activity atMT1 andMT2with agonismat 5-HT1A/1D receptors (Laudon et al., 2012). Piromela-tine was shown to have both hypnotic and antinocicep-tive effects by electroencephalogram (EEG) recordingsand an animal model of neuropathic pain, partial sciaticnerve ligation (Liu et al., 2014). The drug was found toincrease NREM sleep and decrease wakefulness inpartial sciatic nerve ligation mice. Finally, the investi-gators demonstrated that the effect could be blocked bypreadministration of a melatonin receptor antagonist, a5-HT1A receptor antagonist, or an opiate receptorantagonist (Liu et al., 2014), implicating these receptorsin the mechanism of action of the drug.

In 2013, Neurim Pharmaceuticals (Tel-Aviv, Israel)announced positive results from a phase II randomizedclinical trial (N = 120) of piromelatine in primaryinsomnia (Neurim Pharmaceuticals, 2013). Activetreatment with piromelatine 20 or 50 mg/day over4 weeks resulted in significantly improved wake aftersleep onset, sleep efficiency, and total sleep time. TheClinicaltrials.gov database lists a study currentlyrecruiting patients entitled Safety and Efficacy ofPiromelatine in Mild Alzheimer’s Disease Patients(ReCOGNITION); it also lists a completed study enti-tled The Effect of Neu-P11 on Symptoms in Patientswith D-IBS. These studies indicate that Neurim Phar-maceuticals is exploring piromelatine’s potential effi-cacy in myriad conditions, including irritable bowelsyndrome and Alzheimer’s disease.

X. Conclusions

In the last 20 years, preclinical and clinical researchon sleep has expanded tremendously. The study ofknockoutmice for specific receptors has generated novelscientific knowledge of the unique role of each receptorin the regulation of sleep, the application of optogeneticsto the study of sleep has elucidated new circuits, and thediscovery of clock genes has generated insight into thecellular and molecular mechanisms that regulate sleephomeostasis.

In parallel, clinical studies have investigated howsleep architecture is differentially impaired in variousneuropsychiatric diseases (including major depressivedisorder, posttraumatic stress disorder, and Alzheimerdisease) and the manner in which selective receptors’ligands can improve sleep quality and quantity.

Despite these advancements, BZDs continue to bewidely prescribed, although their use, particularly inthe elderly, is associated with an increased risk of falls,fractures, and emergency hospitalizations. Most or allBZDs and Z-drugs are available as generic drugs; assuch, they are available to providers (private insur-ance companies, universal governmental health care


systems) for a very low cost compared with innovativehypnotics (Tannenbaum et al., 2015; Goreveski et al.,2012). Innovative drugs cannot compete with the priceof BZDs, discouraging academia and pharmaceuticalresearch companies from investing in sleep medicine.Clinicians resort to prescribing drugs off-label, althoughthese compounds often lack a strong evidence base fortheir use.Substantial opportunity remains for pipelines that

target the unmet needs in the insomnia market. Medi-cines with comparable efficacy and improved long-termsafety would hold a competitive advantage over currentfirst-line therapies, especially hypnotic without cognitiveside-effects or not causing motor impairments the nextday. Similarly, drugs that improve sleep quality byaugmenting SWS would be viewed favorably by physi-cians. Moreover, drugs that selectively improve sleep inspecific diseases would be also a new avenue for apersonalized medicine.Advancing drug discovery for insomnia and sleep

disorders requires that the industry, in collaborationwith regulatory authorities, clinical experts, and pa-tient communities, engage in promoting and requiringbetter treatment of this condition. Moreover, there is aneed to better define and agree on the nosology of sleep-related illnesses: the classifications of patient popula-tions and the types of outcomes, other than sleepparameters, to be monitored among clients. Researchinto novel hypnotics may bolster the growing concep-tion that sleep disorders are an integral part of, ratherthan secondary to, diseases such as depression andAlzheimer’s (Wafford and Ebert, 2008). Since theburden of insomnia and sleep disorders will likelyincrease in coming decades due to the aging of thepopulation and the growing use of computer technol-ogies (Fossum et al., 2014), research on novel hypnoticsshould be considered a priority.

Acknowledgments

We acknowledge Martina Dick for technical help in Fig. 1.

Authorship Contributions

Wrote or contributed to the writing of the manuscript: Atkin, Comai,Gobbi.

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