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 ] 33 decreasing both time to sleep onset and increasing total sleep time in patients with insomnia compared with placebo in three Phase 3 clinical trials. 24,25 Herring et al evaluated the efficacy of suvorexant at Month 3 of administration to participants in two separate trials, 24 whereas Michelson et al evaluated the safety and tolerability of suvorexant at one year of administration to participants. 25 Efficacy for the trials was assessed by a variety of primary and secondary endpoints that included sleep diaries, subjective total sleep time (sTST), subjective time to sleep onset (sTSO), subjective wake after sleep onset (sWASO), wake after sleep onset (WASO), subjective quality of sleep (sQUAL), subjective refreshed feeling on waking (sFRESH), subjective number of awakenings (sNAW), and latency to onset of persistent sleep (LPS). The former two trials demonstrated that suvorexant 30mg and 40mg was superior to placebo by improving sleep maintenance, measured by sTST and WASO, at Months 1 and 3 for both. The third trial showed that after one month, suvorexant improved sTST (38.7min) versus placebo (16min), and sTSO was also improved with suvorexant (-18min) versus placebo (-8.4min). Although these trials excluded subjects if they had other sleep disorders, confounding neurologic disorders, current major affective or psychotic psychiatric illness, substance abuse, or an unstable medical condition, we investigated the efficacy of suvorexant in psychiatric patients with concomitant use of psychotropic drugs and/or with medical complications and found improvement in quality of sleep using the PSQI self-report questionnaire. It is possible that this efficacy reduced severity of anxiety and depression caused by sleeping disorders in our participants. Prolactin secretion. There has been controversy over the effect of orexin on the hypothalamic control of prolactin secretion. Russell et al 26 reported that intracerebroventicular (i.c.v.) administration of orexin profoundly suppressed plasma prolactin in male rats, and the inhibition of prolactin secretion by orexin is not entirely reversed by the administration of the dopamine D 2 antagonist domperidone, suggesting that other pathways are involved. Pituitary prolactin release is under tonic inhibition from tuberoinfundibular (TIDA) dopamine. Orexin may affect multiple conflicting pathways. For example, it densely innervates adrenergic, histaminergic, and serotogenic neurons that can increase prolactin secretion via the TIDA, while acting on neuropeptide Y (NPY) neurons, which may stimulate the TIDA and thus decrease prolactin secretion. Orexin may stimulate prolactin-inhibitory factors (PIFs) or inhibit prolactin- releasing factors (PRFs) that are independent of the TIDA. Samson et al 27 observed that a dose of the OX1R antagonist was capable of abolishing the ACTH response to immobilization stress TABLE 2. PSQI, GAD-7 and PHQ-9 scores for subjects with follow-up Data OUTCOME SCORE TIME POINT BASELINE WEEK 2 P WEEK4 P PSQI Component 1 2.07±0.17 1.31±0.17 †† 1.28±0.19 †† Component 2 1.93±0.23 1.45±0.23 NS 1.21±0.25 NS Component 3 1.62±0.25 1.10±0.24 NS 0.83±0.21 † Component 4 1.78±0.26 1.14±0.25 NS 0.93±0.23 † Component 5 1.07±0.10 0.86±0.07 NS 0.83±0.09 NS Component 6 2.59±0.20 3 † 3 † Component 7 1.21±0.22 1.14±0.18 NS 1.07±0.19 NS Global Component 12.21±0.85 10.03±0.89 NS 9.14±0.79 † GAD-7 Total 10.52±1.19 7.76±1.15 NS 5.72±1.10 †† PHQ-9 Total 13.97±1.44 10.45±1.25 NS 8.79±1.25 †† Values are mean ± standard error (SE) unless otherwise specified. †=p<0.05 and ††=p<0.01 are for intragroup comparisons for each time point relative to the baseline scores. PSQI=Pittsburg Sleep Quality Index; GAD=generalized anxiety disorder; PHQ=Patient Health Questionnaire; NS=not significant TABLE 3. Prolactin, insulin, cortisol, noradrenaline, white blood cell count, and pulse rate levels with Week 8 follow-up data and evaluation. SAMPLE VISIT BASELINE WEEK 4 WEEK 8 Prolactin, ng/mL Male subjects 16.7±3.1 20.0±4.0 19.0±2.4 Female subjects 43.1±13.8 33.6±8.4 35.5±8.3 Combined 31.9±8.3 27.9±5.2 28.5±5.1 Insulin, µU/mL 18.0±4.8 20.7±7.0 7.9±0.9 Cortisol, µg/dL 17.0±0.9 14.9±0.9 14.0±0.7 Noradrenaline, ng/mL 0.50±0.07 0.41±0.08 0.39±0.10 White blood cell count, µL 7027±388 6438±408 5896±406 Pulse rate, beats/min 88.0±2.7 81.1±1.9 81.3±1.6

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