Sentra PM (a Medical Food) and Trazodone in the Management of Sleep Disorders

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Abstract

Sleep disorders are a common and poorly treated disease state. This double blind, four arm placebo-controlled, randomized trial compared (1) low dose trazodone, (2) Sentra PM, a neurotransmitter based medical food, (3) the joint administration of trazodone and the medical food Sentra PM and (4) placebo. There were 111 subjects studied in 12 independent sites. Subjects underwent baseline screening, informed consent and an initial sleep questionnaire. After 14 days subjects underwent a second evaluation by questionnaire. At baseline and Day 14 the subjects underwent 24 hour ECG recordings that were analyzed in the frequency domain of heart rate variability. The specific high frequency parasympathetic autonomic nervous system activity was analyzed. The primary endpoints were sleep latency and parasympathetic autonomic nervous system improvement in sleeping hours. The results showed improvement in sleep latency for the Sentra PM and combination of Sentra PM and trazodone (−41 and −56 minutes P < 0.001). There was an improvement in quality of sleep for the amino acid formulation Sentra PM and the combination (3.86 and 6.48 Likert units on a 10 point scale P < 0.001). There was an activation of circadian activity percent at night in the medical food and combination groups while there was no change in parasympathetic activity in either the placebo or trazodone group. These data indicate that Sentra PM can improve the quality of sleep, the response to trazodone as a sleep medication and parasympathetic autonomic nervous system activity.

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Most cited references 46

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Serotonin control of sleep-wake behavior.

Simona Monti (2011)

Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT(1-7). The 5-HT(1A) and 5-HT(1B) receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT(3) receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT(6) and 5-HT(7) receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT(2A) and 5-HT(2C) receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT(7) receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT(1A) receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT(1B) (CP-94253), 5-HT(2A/2C) (DOI), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94235), 5-HT(2C) (RO 60-0175), 5-HT(2A/2C) (DOI, DOM), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT(2A/2C) receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT(2A) receptor antagonists volinanserin and pruvanserin and of the 5-HT(2A) receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT(2A) receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT(2A) antagonists or 5-HT(2A) inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia. Copyright © 2010 Elsevier Ltd. All rights reserved.

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Circadian profile of cardiac autonomic nervous modulation in healthy subjects: differing effects of aging and gender on heart rate variability.

H Katus, Axel Brandes, Uwe K H Wiegand … (2003)

Circadian Profile of Heart Rate Variability. Although heart rate variability (HRV) has been established as a tool to study cardiac autonomic activity, almost no data are available on the circadian patterns of HRV in healthy subjects aged 20 to 70 years. We investigated 166 healthy volunteers (81 women and 85 men; age 42 +/- 15 years, range 20-70) without evidence of cardiac disease. Time-domain HRV parameters were determined from 24-hour Holter monitoring and calculated as hourly mean values and mean 24-hour values. All volunteers were fully mobile, awoke around 7 A.M., and had 6 to 8 hours of sleep. Circadian profiles of vagus-associated HRV parameters revealed a marked day-night pattern, with a peak at nighttime and a plateau at daytime. The characteristic nocturnal peak and the day-night amplitude diminished with aging by decade. Estimates of overall HRV (geometric triangular index [TI], SD of NN intervals [SDNN]) and long-term components of HRV (SD of the averages of NN intervals for all 5-min segments [SDANN]) were low at nighttime and increased in the morning hours. There was a significant decline of 24-hour values of all HRV parameters (P < 0.001) and a strong negative correlation (P < 0.001) with increasing age. Mean 24-hour RR interval (P < 0.001), SDNN, mean SD of NN intervals for all 5-minute intervals (SDNNi), and SDANN (all P < 0.01) were significantly higher in men. Younger men also exhibited significantly higher values for vagus-associated parameters (root mean square successive difference [rMSSD], P < 0.05; SDNNi, P < 0.01); however, gender differences diminished with increasing age. Normal aging is associated with a constant decline of cardiac vagal modulation due to a significant decrease of nocturnal parasympathetic activity. The significant gender-related difference of HRV decreases with aging. These findings emphasize the need to determine age-, gender-, and nycthemeral-dependent normal ranges for HRV assessment.

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Relationship between chronic painful physical condition and insomnia.

Maurice M Ohayon (2005)

A chronic painful physical condition (CPPC) can be a major cause of sleep disturbances. Few community-based surveys examined the specific relationship between these two conditions. Eighteen thousand, nine hundred and eighty participants aged 15 years or older from five European countries (the United Kingdom, Germany, Italy, Portugal and Spain) and representative of approximately 206 millions Europeans were interviewed by telephone. The interview included questions about sleeping habits, health, sleep and mental disorders. Painful physical conditions were ascertained through questions about medical treatment, consultations and/or hospitalizations for medical reasons and a list of 42 diseases. A painful physical condition was considered chronic when it lasted at least six months. Insomnia symptoms were defined as difficulty initiating or maintaining sleep or non-restorative sleep, present at least three nights per week, lasting at least one month, and accompanied by daytime consequences. (1) The point prevalence of at least one CPPC was set at 17.1% (95% CI: 16.5-17.6%) in the sample. (2) Difficulty initiating sleep was found in 5.1% (95% CI: 4.8-5.4%) of the sample, disrupted sleep in 7.5% (95% CI: 7.2-7.9%); early morning awakenings in 4.8% (95% CI: 7.2-7.9%) and non-restorative sleep in 4.5% (95% CI: 4.2-4.8%). (3) More than 40% of individuals with insomnia symptoms reported at least one CPPC. (4) CPPC was associated with more frequent difficulty or inability to resume sleep once awake and a shorter sleep duration. (5) In middle-aged subjects (45-64 years of age), CPPC was associated with longer insomnia duration. At any age, insomnia with CPPC was associated with a greater number of daytime consequences (average of four consequences) than in insomnia without CPPC (average of 2.3 consequences). (6) In multivariate models, CPPC, especially backaches and joint/articular diseases, were at least as importantly associated with insomnia than were mood disorders with odds ratios ranging from 4.1 to 5.0 for backaches and from 3.0 to 4.8 for joint/articular diseases. CPPC is associated with a worsening of insomnia on several aspects: a greater number of insomnia symptoms, more severe daytime consequences and more chronic insomnia situation. CPPC plays a major role on insomnia. Its place as major contributive factor for insomnia is as much important as mood disorders.

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Author and article information

Journal

Journal ID (nlm-ta): J Cent Nerv Syst Dis

Journal ID (iso-abbrev): J Cent Nerv Syst Dis

Title: Journal of Central Nervous System Disease

Publisher: Libertas Academica

ISSN (Electronic): 1179-5735

Publication date Collection: 2012

Publication date (Electronic): 23 April 2012

Volume: 4

Pages: 65-72

Author notes

All authors are employees or consultants of Targeted Medical Pharma (TMP). TMP is also the institution at which the data was compiled and prepared for this manuscript.

Corresponding author email: weshell@ 123456ptlcentral.com