Innovations In Clinical Neuroscience

MAR-APR 2017

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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Innovations in CLINICAL NEUROSCIENCE [ V O L U M E 1 4 , N U M B E R 3 – 4 , M A R C H – A P R I L 2 0 1 7 ] 31 producing neurons (orexin neurons) project their axons throughout the entire brain, excluding the cerebellum, 4,5 which suggests that their functions are varied. Particularly, dense projections of orexin neurons are observed in the serotonergic dorsal raphe nucleus (DR), noradrenergic locus coeruleus (LC), and histaminergic tuberomammillary nucleus (TMN), and all of these nuclei are involved in promoting arousal. 6 On the other hand, orexin neurons receive abundant input from the limbic system and also have reciprocal links with hypothalamic arcuate (Arc) nucleus, 4,7 which regulates feeding behavior. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues, such as leptin, ghrelin, and glucose, suggest that these neurons have a role as a link between the energy homeostasis and vigilance states. 8 Consistently, deficiencies of orexin function found in humans and animals produce characteristic symptoms of the sleep disorder narcolepsy 9,10 and cause abnormalities in energy homeostasis and reward systems. 11 In addition, the orexin system regulates autonomic functions, such as blood pressure and heart rate, 12,13 and neuroendocrine systems, including the hypothalamic-pituitary- adrenal (HPA) axis. 14,15 When orexins are administered centrally to rodents, they elevate sympathetic tone, metabolic rate, food intake, locomotor activity, and wakefulness, and their neuroendocrine effects include a lowering of plasma prolactin and growth hormone and an increase in the levels of corticotropin and cortisol, insulin, and luteinizing hormone. 16 These findings demonstrate that orexin neurons play a critical, adaptive role in the coordination of central and peripheral states according to the environmental changes, which is beneficial for survival in nature. The physiological roles of orexin have encouraged pharmaceutical companies to develop drugs targeting orexin receptor agonists or antagonists as treatment for sleep-wake cycle disorders, such as narcolepsy and insomnia, and might also be useful in novel treatments for obesity, eating disorders, or other autonomic/metabolic disorders. 17 Suvorexant was approved in late 2014 by the United States Food and Drug Adminstration (FDA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA) for the treatment of insomnia characterized by difficulty achieving and/or maintaining sleep. Suvorexant is a dual orexin receptor antagonist (DORA) and is first drug in its class to reach the market. 18,19 Suvorexant has been generally effective and well tolerated; however, its pharmacological properties remains unverified in a "real- world" clinical setting. The aim of this study was to investigate the neuroendocrine, sympathetic, and metabolic responses to suvorexant associated with insomnia in psychiatric inpatients. METHODS Subjects. Psychiatric inpatients treated with suvorexant, 15- or 20mg per night, for any type of sleep disorder were eligible to enter the study. Use of psychiatric medication, such as antipsychotics, mood stabilizers, antidepressants, and antianxiety/ hypnotics, was permitted. Diagnosis of mental and behavioral disorders were made according to the International Statistical Classification of Disease and Related Health Problems 10th Revision (ICD-10). 20 Throughout the observation period, the exclusion criteria included an alternation in psychiatric medication and/or any medical treatment that directly affected the patient's sleeping or neuroendocrine and metabolic systems. Under these criteria, subjects were enrolled consecutivel, and a total of 40 subjects were studied prospectively from December 2014 to April 2016 at Kusatsu Hospital in Hiroshima, Japan. Outcome measures and statistical methods. Quality of sleeping using the Pittsburgh Sleep Quality Index (PSQI), 21 severity of anxiety using the Generalized Anxiety Disorder-7 (GAD-7), 22 and severity of depression using the Patient Health Questionnaire-9 (PHQ-9) 23 were evaluated at baseline and two and four weeks following suvorexant treatment. Fasting plasma samples for analysis of prolactin, insulin, cortisol, and noradrenaline were drawn through routine practice and measured together with white blood cell count at baseline, Week 4, and Week 8 during suvorexant treatment. The average pulse rate was calculated by routine vital measurement at 9:00AM on three consecutive days— the day before, the day of, and the day after each of the following visits: baseline, Week 4, and Week 8. The collected average pulse rate data were assessed together with the other laboratory test data. Multiple comparisons of the measured values at baseline, Week 2, and Week 4 or at baseline, Week 4, and Week 8 were individually performed with repeated-measured ANOVA, followed by post-hoc analysis using Boneferroni adjustment, and considered statistically significant at P<0.05. The data were presented as means ± standard error (SE). Ethical approval. The ethics committee of Kusatsu Hospital approved this study, and written informed consent was obtained from all participants. RESULTS Sample characteristics and treatment disposition. Subjects consisted of 24 men (2 with mild cognitive impairment, 7 with alcoholic psychosis, 7 with schizophrenia/schizoaffective disorder, 7 with mood disorder, and 1 with neurotic/stress-related disorder) with a mean age of 55.4 years; and 16 women (5 with schizophrenia/schizoaffective disorder, 9 with mood disorder, and 2 with neurotic/stress-related disorder) with a mean age of 54.9 years. Of the 40 subjects, two men dropped out of the study for somnolence and fatigue, one man for patient refusal to continue the study at Week 4, and 10 men and one woman for patient discharge at Week 8. The clinical characteristics of subjects taking suvorexant along with concomitant use of psychiatric drugs from baseline to the end observation period are summarized in Table 1. PSQI, GAD-7, and PHQ-9 scores with Week 4 follow-up data and evaluation. Subjective sleep quality scores (Component 1) decreased and use of sleep medication (Component 6) scores increased significantly at Weeks 2 and 4 from baseline; sleep duration (Component 3), habitual sleep efficacy

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