Updates on Nutraceutical Sleep Therapeutics and Investigational Research

Approximately 50% of the population will suffer from a sleep disorder over the course of their lifetime. There is increasing interest in nutraceuticals for these conditions. The quality of the evidence for the safety and effectiveness of using these supplements to treat sleep disorders varies substantially. In this review, we discuss the data about the effectiveness and safety of six commonly used plant-based sleep therapeutics: caffeine, chamomile, cherries, kava kava, L-tryptophan, marijuana, and valerian. We explore both historical uses of each substance and the current state of the literature

Sleep disorders and suicide attempts following discharge from residential treatment

IntroductionSuicide is a significant public health concern and its prevention remains a top clinical priority of the Veterans Health Administration. Periods of transition in care (e.g., moving from inpatient to outpatient care) represent a period of increased risk. Sleep disorders are prevalent amongst Veterans and are modifiable risk factor for suicide. The present study examined the relationship of sleep disorders to time to suicide attempt amongst Veterans known to have attempted suicide in the 180 days following discharge from a Mental Health Residential Rehabilitation Treatment Program.MethodThe present sample was comprised of all Veterans enrolled in services with the Veterans Health Administration known to have attempted suicide following discharge from a Mental Health Residential Rehabilitation Treatment Program during Fiscal Years 13 and 14 (N = 1,489). To create this sample, electronic medical record data were extracted from two VHA data sources: the Corporate Data Warehouse and the Suicide Prevention Application Network.ResultsCox regression models revealed that Veterans with a sleep disturbance (N = 1,211) had a shorter time to suicide attempt than those without a sleep disturbance [Hazard Ratio (HR) = 1.16, CI (1.02–1.32)]. A subsequent Cox regression model including age, insomnia, nightmare disorder, and alcohol dependence revealed that sleep-related breathing disorders [HR = 1.19, CI (1.01–1.38)], alcohol dependence [HR = 1.16, CI (1.02–1.33)], and age group were associated with increased risk.ConclusionFindings indicate that sleep disturbance, primarily driven by sleep-related breathing disorders, was associated with time to suicide attempt in this sample of high-risk Veterans known to have attempted suicide in the 180 days following their discharge from a Mental Health Residential Rehabilitation Treatment Program. These findings reveal an opportunity to reduce risk through the screening and treatment of sleep disorders in high-risk populations

Why Treat Insomnia?

“Why treat insomnia?” This question grows out of the perspective that insomnia is a symptom that should only receive targeted treatment when temporary relief is needed or until more comprehensive gains may be achieved with therapy for the parent or precipitating medical or psychiatric disorders. This perspective, however, is untenable given recent data regarding the prevalence, course, consequences, and costs of insomnia. Further, the emerging data that the treatment of insomnia may promote better medical and mental health (alone or in combination with other therapies) strongly suggests that the question is no longer “why treat insomnia,” but rather “when isn’t insomnia treatment indicated?” This perspective was recently catalyzed with the American College of Physicians’ recommendation that chronic insomnia should be treated and that the first line treatment should be cognitive-behavioral therapy for insomnia (CBT-I)

Suicide Attempts in the 12 Months Following Incident Prescriptions of Sedative-Hypnotic Medications in a Large Healthcare System

Introduction: Both sleep medications in general and insomnia have been associated with suicide risk. We sought to ascertain the frequency of suicide attempt (SA) by patients using any such medications and to provide SA rates by individual medication. Methods: Subjects were receiving care in the US Veterans Health Administration (VHA) with an index (first time) prescription for a sleep medication in 2011, no SAs and no sleep medication prescriptions in 2010, and no additional sleep medication prescribed for 12 months after the incident prescription. Medications included benzodiazepines, z-drugs, ramelteon, sedating antidepressants, and antihistamines in dosages (e.g., 50–100mg of trazodone) and dosing schedules (e.g., excluding 1 day prescriptions) consistent with insomnia treatment. SA frequencies in the 12 months after the index prescription were tabulated by medication. Data were obtained from the VHA Corporate Data Warehouse and the Suicide Prevention Application Network, which captures all VHA veteran SAs known to VHA. SA incidence was calculated according to accepted methods and presented as events per 100,000 person years (PYs) with a 95% confidence interval (CI). Results: 226,482 VHA users had an incident sleep medication prescription, representing 3.4% of VHA users. Among 15 medications identified, the most commonly prescribed were trazadone (24.4%), zolpidem (18.4%), hydroxyzine (15.3%), lorazepam (11.6%), and mirtazapine (8.1%). The total of recorded SAs within one year of incident prescription was N=454, representing 207 SAs per PYs (95% CI=188–227). Those with the highest rate of SA per PY had been prescribed mirtazapine (330), trazadone (296), hydroxyzine (188), zolpidem (178), and lorazepam (180). The lowest rates among medications with at least 10,000 incident prescriptions was observed for temazepam (99), diazepam (117) and amitriptyline (131). Conclusion: The rate of SA following incident sleep medications was similar to that observed in other large veteran cohorts, though there was variability of SA rates across individual medications. An observation is that the incident prescription rate is low compared to expected rates of incident insomnia. Support (If Any): VA Center of Excellence for Suicide Prevention. Disclaimer: The authors’ views or opinions do not necessarily represent those of the Department of Veterans Affairs or the US Government

Effects of a Tart Cherry Juice Beverage on the Sleep of Older Adults with Insomnia: A Pilot Study

This study ascertained whether a proprietary tart cherry juice blend (CherryPharm, Inc., Geneva, NY, USA) associated with anecdotal reports of sleep enhancement improves subjective reports of insomnia compared to a placebo beverage. The pilot study used a randomized, double-blind, crossover design where each participant received both treatment and placebo for 2 weeks with an intervening 2-week washout period. Sleep continuity (sleep onset, wake after sleep onset, total sleep time, and sleep efficiency) was assessed by 2-week mean values from daily sleep diaries and disease severity by the Insomnia Severity Index in a cohort of 15 older adults with chronic insomnia who were otherwise healthy. The tart cherry juice beverage was associated with statistically significant pre- to post-treatment improvements on all sleep variables. When compared to placebo, the study beverage produced significant reductions in insomnia severity (minutes awake after sleep onset); no such improvements were observed for sleep latency, total sleep time, or sleep efficiency compared to placebo. Effect sizes were moderate and in some cases negligible. The results of this pilot study suggest that CherryPharm, a tart cherry juice blend, has modest beneficial effects on sleep in older adults with insomnia with effect sizes equal to or exceeding those observed in studies of valerian and in some, but not all, studies of melatonin, the two most studied natural products for insomnia. These effects, however, were considerably less than those for evidence-based treatments of insomnia: hypnotic agents and cognitive-behavioral therapies for insomnia

The Z-Drugs and Their Association with Suicidality, Mortality, and Overdose: A Systematic Review

Introduction: A link has been suggested between the use of sedative-hypnotic medications and all-cause mortality, particularly accidental death and suicide. The z-drugs (zolpiedem, zaleplon, eszopiclone zopiclone) are non-benzodiazepines that aid in the initiation of sleep by acting on gamma-aminobutyric acid-alpha receptors. Z-drug mechanisms suggestive of suicidality may include: 1) decreased inhibition for acting on impulsive thought, 2) agitation after discontinuation, 3) depression of the central nervous system, 4) and the indication, insomnia. This systematic review examines the potential effects of the z-drugs on suicidal ideation and behavior, traumatic injury, mortality, and accidental poisoning. Methods: On June 20, 2015 a systematic literature review of the PsycINFO and PubMed databases was conducted using the following search term: [(zopiclone OR zolpidem OR zaleplon OR eszopiclone) AND (suicide OR suicidal OR traumatic injury OR mortality OR drug overdose)]. Articles were included if they were available in English, reported human subjects data, original research or analyses of population-based datasets, and included z-drug utilization and at least one of the outcomes of interest as listed in the search terms. Included articles were used to identify additional articles through references. Results: Of 178 abstracts, 147 were excluded if they were: not original research, a case study, a duplicate, or did not report target outcome, z-drug usage, or data allowing interpretation of this relationship. The review covered 31 studies and overall suggested a possible association between exposure to z-drugs, particularly if used outside of clinical guidelines, and increased risk of mortality, drug overdose, and traumatic injury. Conclusion: Z-drugs have demonstrated utility as a sleep aid and may be important in reducing overall mortality associated with sleep disturbance. Yet, they have been associated with increased somnolence and traumatic injury (e.g., motor vehicle accidents), particularly in women and those taking higher doses, resulting in significant dose change forms and relabeling for FDA. Support (If Any): This work was supported, in part, by the VA Advanced Fellowship Program in Mental Health Illness Research and Treatment, VISN 2 Center of Excellence for Suicide Prevention at the Canandaigua VAMC

The Z-Drugs and Their Association with Suicidality, Mortality, and Overdose: A Systematic Review

Introduction: A link has been suggested between the use of sedative-hypnotic medications and all-cause mortality, particularly accidental death and suicide. The z-drugs (zolpiedem, zaleplon, eszopiclone zopiclone) are non-benzodiazepines that aid in the initiation of sleep by acting on gamma-aminobutyric acid-alpha receptors. Z-drug mechanisms suggestive of suicidality may include: 1) decreased inhibition for acting on impulsive thought, 2) agitation after discontinuation, 3) depression of the central nervous system, 4) and the indication, insomnia. This systematic review examines the potential effects of the z-drugs on suicidal ideation and behavior, traumatic injury, mortality, and accidental poisoning. Methods: On June 20, 2015 a systematic literature review of the PsycINFO and PubMed databases was conducted using the following search term: [(zopiclone OR zolpidem OR zaleplon OR eszopiclone) AND (suicide OR suicidal OR traumatic injury OR mortality OR drug overdose)]. Articles were included if they were available in English, reported human subjects data, original research or analyses of population-based datasets, and included z-drug utilization and at least one of the outcomes of interest as listed in the search terms. Included articles were used to identify additional articles through references. Results: Of 178 abstracts, 147 were excluded if they were: not original research, a case study, a duplicate, or did not report target outcome, z-drug usage, or data allowing interpretation of this relationship. The review covered 31 studies and overall suggested a possible association between exposure to z-drugs, particularly if used outside of clinical guidelines, and increased risk of mortality, drug overdose, and traumatic injury. Conclusion: Z-drugs have demonstrated utility as a sleep aid and may be important in reducing overall mortality associated with sleep disturbance. Yet, they have been associated with increased somnolence and traumatic injury (e.g., motor vehicle accidents), particularly in women and those taking higher doses, resulting in significant dose change forms and relabeling for FDA. Support (If Any): This work was supported, in part, by the VA Advanced Fellowship Program in Mental Health Illness Research and Treatment, VISN 2 Center of Excellence for Suicide Prevention at the Canandaigua VAMC

Suicide Attempts in the 12 Months Following Incident Prescriptions of Sedative-Hypnotic Medications in a Large Healthcare System

Introduction: Both sleep medications in general and insomnia have been associated with suicide risk. We sought to ascertain the frequency of suicide attempt (SA) by patients using any such medications and to provide SA rates by individual medication. Methods: Subjects were receiving care in the US Veterans Health Administration (VHA) with an index (first time) prescription for a sleep medication in 2011, no SAs and no sleep medication prescriptions in 2010, and no additional sleep medication prescribed for 12 months after the incident prescription. Medications included benzodiazepines, z-drugs, ramelteon, sedating antidepressants, and antihistamines in dosages (e.g., 50–100mg of trazodone) and dosing schedules (e.g., excluding 1 day prescriptions) consistent with insomnia treatment. SA frequencies in the 12 months after the index prescription were tabulated by medication. Data were obtained from the VHA Corporate Data Warehouse and the Suicide Prevention Application Network, which captures all VHA veteran SAs known to VHA. SA incidence was calculated according to accepted methods and presented as events per 100,000 person years (PYs) with a 95% confidence interval (CI). Results: 226,482 VHA users had an incident sleep medication prescription, representing 3.4% of VHA users. Among 15 medications identified, the most commonly prescribed were trazadone (24.4%), zolpidem (18.4%), hydroxyzine (15.3%), lorazepam (11.6%), and mirtazapine (8.1%). The total of recorded SAs within one year of incident prescription was N=454, representing 207 SAs per PYs (95% CI=188–227). Those with the highest rate of SA per PY had been prescribed mirtazapine (330), trazadone (296), hydroxyzine (188), zolpidem (178), and lorazepam (180). The lowest rates among medications with at least 10,000 incident prescriptions was observed for temazepam (99), diazepam (117) and amitriptyline (131). Conclusion: The rate of SA following incident sleep medications was similar to that observed in other large veteran cohorts, though there was variability of SA rates across individual medications. An observation is that the incident prescription rate is low compared to expected rates of incident insomnia. Support (If Any): VA Center of Excellence for Suicide Prevention. Disclaimer: The authors’ views or opinions do not necessarily represent those of the Department of Veterans Affairs or the US Government